Monica Bandettini di Poggio

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinsons disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Students t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa.

Physical activity and amyotrophic lateral sclerosis: A European population-based case–control study

To assess whether physical activity is a risk factor for amyotrophic lateral sclerosis (ALS).

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an ‘Official MDS translation,’ the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling

Objective: The present study was aimed to enlarge the Italian ALS sample analysed for TARDBP gene mutations. Methods: Genomic DNA from 47 patients, 70 FTD patients and 158 controls was extracted from peripheral blood samples according to a standard protocol. The five coding exons (2–6) of the TARDBP gene and the flanking exon-intron boundaries were analysed by direct sequencing. Using ClustalW2 human TDP-43, protein sequence was aligned with TDP-43 protein sequence of different species. Results: A heterozygous c.1178 C→T transition that leads to a change p.S393L was observed in a 75-years-old male patient and in his two affected siblings. A patients brother had died at 69 years of age after a two-year history of ALS. In FTD patients no mutations were found. Conclusions: We describe a further Italian family with FALS, in which a variant (p.S393L) of the TARDBP gene was identified. Clinical course and phenotypic variability in three affected siblings is presented and relevance for genetic counselling of patients and their families is underlined. At the present state of knowledge, we suggest that the same guidelines established for SOD1 molecular testing could be proposed also for TARDBP analysis in FALS.

Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset

Abstract ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [3H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

Clinical epidemiology of ALS in Liguria, Italy.

Abstract Our objective was to assess the incidence and trends of amyotrophic lateral sclerosis (ALS) in Liguria, a north-west region of Italy, utilizing a prospective design. Liguria (1,615,064 residents in 2010) is the site of a multicentre-multisource prospective population based registry called LIGALS (Liguria Amyotrophic Lateral Sclerosis Registry). All incident ALS cases during the period 2009–2010 were enrolled and followed up. Cases were identified using several concurrent sources. ALS diagnosis was based on the revised El Escorial criteria. One hundred and four cases were enrolled, generating an annual crude incidence of 3.22/100,000 (95% CI 2.66−3.90), with a male/female ratio of 1.34. The annual standardized incidence, age and gender adjusted to the 2001 Italian population, was 2.51. At last observation on 1 March 2012, 45% of patients registered in the LIGALS had died, with a median survival of 45 months from symptoms onset. According to capture-recapture estimation, three patients were unobserved. For both genders, demographic and clinical features were collected. In conclusion, comparing these data to those of epidemiological studies with a similar prospective design, the occurrence of ALS is similar. The observed crude incidence was higher compared to other Italian studies, due in part to a very careful case ascertainment and in part to a high percentage of the elderly in Liguria.

Dopamine-agonist responsive Parkinsonism in a patient with the SANDO syndrome caused by POLG mutation

BackgroundDisorders of oxidative phosphorylation affects 1/5000 individuals and present heterogeneous involvement of tissues highly dependent upon ATP production.Case presentationHere we present the case of a 48-year-old woman carrying a homozygous mutation (p.A899T) in mitochondrial polymerase gamma (POLG) and manifesting with a complex neurological phenotype including Dopamine-agonist responsive Parkinsonism.ConclusionThis case report is further evidence that mitochondrial dysfunction might play a role in Parkinson’s Disease pathogenesis and helps in identification of apparent mutation-specific clinical characteristics. Mutations in POLG should be looked for in cases of Parkinsonism, especially when multisystem neurological involvement is found.

Whole body and cardiac metaiodobenzylguanidine kinetics in Parkinson disease and multiple system atrophy: implications for the diagnostic role of imaging.

Purpose of the Report: This study investigates whether combined analysis of I-123 metaiodobenzylguanidine (MIBG) kinetics in the heart and in the whole body can improve the accuracy of differential diagnosis between idiopathic Parkinson disease (PD) and a Parkinson variant of multiple system atrophy (MSA-P). Materials and Methods: A total of 30 patients with clinical suspicion of PD (n = 16) or MSA-P (n = 14) underwent MIBG whole-body planar imaging. Final diagnosis was confirmed at follow-up. Images were collected 30 minutes and 4 hours after tracer injection. Myocardial uptake was evaluated by measuring heart/mediastinum (H/M) ratio and the percent fraction of the injected dose retained by the heart (calculated by whole-body counts). Tracer washout was measured from both the heart and the whole body. Results: H/M ratio was lower in PD than in MSA-P at early imaging (1.32 ± 0.21 vs. 1.81 ± 0.46, respectively, P < 0.01), although a large overlap in individual data was observed. By contrast, % of injected dose taken up by the heart documented a large difference between PD and MSA-P (0.97% ± 0.51% vs. 1.91% ± 0.66% of the dose, P < 0.01), and a very small overlap in individual values. There was no difference in the heart washout between the 2 Groups (31% ± 13% vs. 32% ± 15%, P = 0.9), while tracer loss from the whole body was higher in PD than in MSA-P (29% ± 12% vs. 19% ± 10%, P < 0.01). Conclusions: PD and its correlated global postganglionic dysfunction alter MIBG kinetics in the heart and in the whole body. Image analysis accounting for tracer kinetics in the whole body may improve the diagnostic accuracy of this test in patients with suspected PD or MSA-P.

Molecular chaperones in the pathogenesis of amyotrophic lateral sclerosis : the role of HSPB1

Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion‐like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome‐maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild‐type protein in a stable dimer and resulting in a loss of chaperone‐like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.

Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: An update of LIGALS register

Abstract Our objectives were: (1) to assess amyotrophic lateral sclerosis (ALS) incidence and its trend over time in Liguria, an Italian north-western region, performing an analysis of data prospectively collected from 1 January 2009 to 31 December 2014; (2) to determine the mean and median survival in the 2009–2014 Ligurian ALS incident cases; and (3) to evaluate the presence of disease prognostic factors. The Liguria Register for ALS (LIGALS) is an ongoing, multicentre prospective register enrolling all ALS incident cases in Liguria. Cases were identified using several concurrent sources. ALS diagnosis was based on El Escorial revised criteria (EEC-R). Two hundred and ninety-eight patients were enrolled in this study. The mean annual crude incidence rate in the 2009–2014 period was 3.11/100,000 population (95% CI 2.77–3.49); the point prevalence at 31 December 2014 was 7.85/100,000 (95% CI 6.54–9.36) population. Survival analysis demonstrated a median survival from symptom onset of 37.0 months (95% CI 32.0–42.0). In conclusion, ALS crude incidence in Liguria is higher compared to other Italian regions. Clinical and epidemiological data are comparable with those of the Italian ALS population. Survival analysis showed that higher age at onset, bulbar onset, definite EEC-R diagnostic category and a shorter diagnostic delay are related with worse outcomes.