Marcello Moccia

The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients.

Background The variability in the clinical phenotype of Parkinson’s disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients. Methods We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored. Results The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant. Conclusion Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.

Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients

Background Non-motor symptoms are very common among patients with Parkinsons disease since the earliest stage, but little is known about their progression and their relationship with dopaminergic replacement therapy. Methods We studied non-motor symptoms before and after 2 years from dopaminergic therapy introduction in ninety-one newly diagnosed previously untreated PD patients. Results At baseline, nearly all patients (97.8%) referred at least one non-motor symptom. At follow-up, only few non-motor symptoms significantly changed. Particularly, depression and concentration became less frequent, while weight change significantly increased after introduction of dopamine agonists. Conclusions We reported for the first time a 2-year prospective study on non-motor symptoms before and after starting therapy in newly diagnosed PD patients. Even if non-motor symptoms are very frequent in early stage, they tend to remain stable during the early phase of disease, being only few non-motor symptoms affected from dopaminergic therapy and, specifically, by the use of dopamine agonists.

Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson's disease patients

BACKGROUND Anxiety is a common non-motor symptom among patients with Parkinsons disease (PD). Although the etiology of anxiety in PD is likely to be multifactorial, a dysfunction in the dopaminergic system might be implicated in its pathogenesis. The aim of our study was to investigate a possible dopaminergic mechanism involved in anxiety in newly diagnosed never-medicated PD patients using SPECT and ¹²³I-FP-CIT as the dopamine transporter ligand. METHODS Thirty-four newly diagnosed, untreated PD patients with asymmetric motor symptoms were included in the study: 17 patients with right- and 17 with left-motor onset, matched for age, disease duration and motor disability constituted the group. They were all evaluated for anxiety and depression and underwent an SPECT with ¹²³I-FP-CIT. Dopamine transporter (DAT) availability values for right and left caudate and putamen were calculated and compared between patients with and without anxiety. Regression analyses were also performed in order to correlate DAT availability with the severity of the anxiety symptoms. RESULTS Comparison between PD patients with and those without anxiety revealed significant differences of DAT availability in all the examined regions except the right putamen. In the group of patients considered as a whole, a significant correlation was found between increased anxiety severity and decreased DAT availability in right caudate. CONCLUSIONS We reported an association between nigrostriatal DAT availability deficits and anxiety symptoms in newly diagnosed, untreated PD patients. Our results suggest that hypofunction of the nigrostriatal dopaminergic system may represent one of the functional anomalies involved in anxiety in PD from the earliest stages of disease and irrespective of any therapy.

Mild Cognitive Impairment in newly diagnosed Parkinson's disease: A longitudinal prospective study

INTRODUCTION In PD, Mild Cognitive Impairment (PD-MCI) occurs since early stages of disease. The aims were to assess presence of PD-MCI in untreated, drug-naive PD patients, and to follow-up the sample over 4 years to ascertain evolution of neurocognitive profile. METHODS Seventy-six patients underwent neuropsychological testing at baseline (T0), and after 2 (T1:n = 62) and 4 years (T2:n = 55). Diagnosis of PD-MCI and PD-associated dementia (PDD) was made according to current consensus criteria. RESULTS PD-MCI occurred in 25/76 patients (32.9%) at baseline, and 4 of them reverted from PD-MCI to Normal Cognition (Reverters), 7 remained stable (Non-Reverters) and 2 developed PDD at T2; 12 patients were lost to the follow-up. Among the 51 patients with normal cognition (PD-CN) at T0, 27 had normal cognition at T2 (5 of them were Reverters with respect to diagnosis at T1), 5 had MCI at T1 and T2 (Non-Reverters), 9 had MCI at T2 only, whereas 1 developed PDD; 9 patients were lost to the follow-up. At baseline, Reverters (n = 9) had younger age at onset and better performance on constructional visuospatial task than Non-Reverters (n = 12). Compared to patients without PD-MCI at all evaluations (n = 19), Reverters had poorer performance on verbal immediate recall and attention tasks and higher level of apathy at T0. Reduced performance on the Stroop Test at baseline predicted PD-MCI at T2. CONCLUSION Executive dysfunctions predicted development of PD-MCI after few years from onset. Reversal from PD-MCI to PD-CN was related to young age at onset and high level of apathy at baseline evaluation.

Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study.

Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinsons disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug‐naïve untreated PD patients with or without clinically significant apathy.

Gender differences in non-motor symptoms in early, drug naïve Parkinson’s disease

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson’s disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ2 exact test; multiple comparisons were corrected with the Benjamini–Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

Hearing Impairment in Parkinson's Disease: Expanding the Nonmotor Phenotype

The objective of this study was to evaluate hearing impairment in patients affected by Parkinsons disease compared with hearing scores observed in normal age‐ and sex‐matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinsons disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinsons Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory‐evoked potentials. Healthy age‐ and sex‐matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age‐dependent high‐frequency hearing loss in patients with Parkinsons disease compared with both normative values and values for healthy age‐ and sex‐matched controls (75/106 [71%], χ2 = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ2 = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory‐evoked potentials were normal in all patients. Our patients with Parkinsons disease showed age‐dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinsons disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α‐synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise‐induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinsons disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis.

Restless Legs Syndrome is a Common Feature of Adult Celiac Disease

Restless legs syndrome (RLS) is a common neurological condition, frequently idiopathic, sometimes associated with specific disorders such as iron deficiency. We investigated RLS prevalence in celiac disease (CD), an autoimmune disease characterized by several features such as malabsorption‐related iron deficiency anemia and peripheral neuropathy. We screened a population of 100 adult CD patients for CD features, iron metabolism, clinical and neurological conditions, and enrolled 100 age‐ and sex‐matched controls in the general population. RLS was ascertained in CD patients and controls by both the presence of the four essential International RLS Study Group diagnostic criteria and neurological examination. The International RLS Study Group rating scale was used to measure RLS severity. We found a 31% prevalence of RLS in the CD population that was significantly higher than the prevalence in the control population (4%; P < 0.001). The average severity of RLS in CD population was moderate (17 ± 6.5). In the CD population, no significant correlation was found between RLS and either gluten‐free diet or iron metabolism, despite hemoglobin levels were significantly lower in CD patients with RLS than without RLS (P = 0.003). We found no correlation between RLS and other possible causes of secondary RLS, including signs of peripheral neuropathy, pregnancy, end‐stage renal disease, and pharmacological treatments.Our study broadens the spectrum of neurological disorders associated with CD and indicates that RLS should be sought for in all patients with CD.

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression:

Background: Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing–remitting (RR). Objective: To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. Methods: The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. Results: 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Conclusion: Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS.

Gender differences in non-motor symptoms in early Parkinson's disease: A 2-years follow-up study on previously untreated patients

BACKGROUND We recently showed specific sex-related patterns of non motor symptoms (NMS) in early, drug-naïve PD patients. However, to date studies investigating gender-related effects of dopaminergic treatment on NMS in early PD are lacking. METHODS In the present study, we first report a prospective assessment of gender-related differences in the spectrum of NMS before (baseline) and after starting dopaminergic therapy (2-year follow-up) in a large cohort of newly diagnosed PD patients. Differences in NMS frequency between baseline and follow-up were evaluated by McNemar test. Spearmans rank test was employed to explore interactions between NMS and drug treatment. RESULTS One-hundred and thirty four PD patients (86M and 48W) were included in the present study. At 2-year follow-up, Sadness/blues presented a significant percentage reduction as compared to baseline in both sexes, while Urgency, Daytime sleepiness, Weight change and Sex drive presented a significant percentage increase only in men. At follow up men complained of a greater number of NMS as compared to women. Occurrence of Weight change was related to therapy in both sexes. Male gender was found to be a risk factor for developing Dribbling and Nocturia, irrespective of therapy and clinical features. CONCLUSIONS In conclusion, our study showed that mood symptoms improved after the introduction of therapy in both sexes, while men appeared to be more prone to develop some NMS possibly linked to dopaminergic treatment.