Anna De Rosa

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.

PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family

SYNJ1 has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same SYNJ1 homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the SYNJ1 homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.

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.

PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of Parkinsonism

We analyzed the PINK1 gene in 58 patients with early‐onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good response to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinsons disease and 3 further relatives were reported affected, according to an autosomal dominant transmission.

Link between non-motor symptoms and cognitive dysfunctions in de novo, drug-naive PD patients

Little is known about the relationship between cognitive dysfunctions and the non-motor complex in subjects with newly diagnosed untreated Parkinson’s disease (PD). The aim of this study was to explore the association between non-motor symptoms (NMS) and cognitive dysfunctions in an incident cohort of de novo, drug-naive, PD patients. Sixty-six non-demented, early, untreated PD patients completed a semi-structured interview on NMS and a battery of neuropsychological tests that assess verbal memory, visuospatial abilities, and attention/executive functions. Scores were age- and education-corrected. Patients who failed at least two tests for each cognitive domain were diagnosed as having mild cognitive impairment (MCI). All but three (95.4%) PD patients complained of at least one NMS. A total of 37.8% was diagnosed with MCI. There was a relationship between sleep-NMS and cognitive dysfunctions. Specifically, both REM behavioral sleep disorders (RBD) and insomnia were associated with lower scores on several cognitive tests. Moreover, RBD was closely related to MCI. NMS and MCI are very common even in the early phase of PD, before patients are treated. Given the correlation between sleep disturbances and cognitive impairment, it is possible that sleep symptoms in PD patients might be considered as an early marker of dementia.

Guidelines for the diagnosis of dementia and Alzheimer's disease

SIN DOCUMENT*The Dementia Study Group is co-ordinated by Sandro Sorbi andincludes: Margherita Alberoni, Milan; Pasquale Alfieri, SommaVesuviana (NA); Serena Amici, Perugia; Daniele Antana, Rome;Ildebrando Appollonio, Monza (MI); Stefano Avanzi,Castelgoffredo (MN); Antonella Bartoli, Pescara; BrunoBergamasco, Turin; Laura Bracco, Florence; Amalia Bruni,Lamezia Terme (CZ); Orso Bugiani, Milan; Paolo Caffarra, Parma;Carlo Caltagirone, Rome; Antonio Carolei, L’Aquila; Anna RosaCasini, Rome; Luciana Ciannella, Benevento; Antonietta Citterio,Pavia; Antonio Daniele, Rome; Graziella D’Achille, Isernia;Giuseppe Del Curatolo, Grosseto; Grazia Dell’Agnello, Pisa;Daniele Durante, Parma; Elisabetta Farina, Milan; Patrizia Ferrero,Turin; Paolo Forleo, Florence; Guido Gainotti, Rome; PaoloGabriele, Cassino (FR); Emanuela Galante, Castelgoffredo (MN);Virgilio Gallai, Perugia; Roberto Gallassi, Bologna; MaddalenaGasparini, Milan; Bernardino Ghetti, Indianapolis (USA); GiorgioGiaccone, Milan; Floriano Girotti, Milan; Luigi Grimaldi, Milanand Caltanisetta; Serenella Grioli, Catania; Bianca MariaGuarnieri, Pescara; Stefano Grottoli, Fossombrone (PS); FrancescoIemolo, Ragusa; Stefania Latorraca, Florence; Francesco Le Pira,Catania; Gian Luigi Lenzi, Rome; Sebastiano Lorusso, Rimini;Claudio Mariani, Milan; Gabriella Marcon, Udine; VincenzoMascia, Carbonia (CA); Simonetta Mearelli, L’Aquila; MariaMorante, Senigallia (AN); Michela Morbin, Milan; MassimoMusicco, Segrate (MI); Ettore Nardelli, Verona; Paolo Nichelli,Modena; Alessandro Padovani, Brescia; Marco Paganini, Florence;Roberta Pantieri, Bologna; Pietro Parisen, Vicenza; LucillaParnetti, Perugia; Bruno Passerella, Brindisi; Carla Pettenati, Rho(MI); Silvia Piacentini, Florence; Federico Piccoli, Palermo; CarloPiccolini, Perugia; Gilberto Pizzolato, Padova; LeandroProvinciali, Ancona; Nicola Pugliese, Salerno; Francesco Redi,Arezzo; Rosa Maria Ruggieri, Palermo; Umberto Ruggiero,Naples; Marco Saetta, Siracusa; Rudolf Schoenuber, Bolzano;Maria Caterina Silveri, Rome; Sandro Sorbi, Florence; GiuseppeSorrentino, Naples; Patrizia Sucapane, L’Aquila; Andrea Stracciari,Bologna; Massimo Tabaton, Genova; Fabrizio Tagliavini, Milan;Vito Toso, Vicenza; Francesco Valluzzi, Putignano Noci (BA)S. Sorbi ( )Department of Neurological and Psychiatric SciencesUniversity of FlorenceViale Morgagni 85, I-50131 Florence, Italy

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.

Postganglionic sudomotor denervation in patients with multiple system atrophy

Objective: To evaluate postganglionic autonomic involvement in multiple system atrophy (MSA). Methods: We quantified sudomotor innervation in skin biopsy of 29 patients with MSA (19 male and 10 female; age 60.0 ± 7.7 years) and 29 age- and sex-matched healthy subjects. Samples were obtained from thigh and leg and, in 20 out of the 29 cases, also from fingertip. Dysautonomic complaints were evaluated by SCOPA-AUT, a self-administered questionnaire. Sudomotor function was evaluated in a subgroup of patients by the silastic imprint test. Skin samples were processed by indirect immunofluorescence using pan-neuronal and selective cholinergic markers. Total length of sudomotor nerves was measured on digital confocal images using a semiautomated morphometric approach. Results: Measurements of sudomotor nerve density (total length of nerve per volume of glandular tissue) favorably correlated to values obtained using a stereologic unbiased method. Sudomotor nerve density was lower in patients compared to controls in all the examined sites (0.9 ± 0.2 vs 1.9 ± 0.4 nm/μm3, p < 0.001, in fingertip; 0.7 ± 0.2 vs 1.9 ± 0.5 nm/µm3, p < 0.001, in thigh; 0.6 ± 0.2 vs 1.8 ± 0.4 nm/µm3, p < 0.001, in leg). Conclusions: Our data support the hypothesis that postganglionic impairment occurs in MSA and may contribute with the coexisting degeneration of central structures to the development of dysautonomic disorders in this condition.

Antiphospholipid-Related Chorea

Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL-related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is β2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment.