Pierfrancesco Pugliese

Prefrontal alterations in Parkinson's disease with levodopa-induced dyskinesia during fMRI motor task.

Levodopa‐induced dyskinesia represents disabling complication of long‐term therapy with dopaminergic drugs in treating Parkinsons disease (PD). Recently, our group demonstrated that PD patients with levodopa‐induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa‐induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa‐induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

Increased prefrontal volume in PD with levodopa‐induced dyskinesias: A voxel‐based morphometry study

Levodopa‐induced dyskinesias represent disabling complications from long‐term therapy with dopaminergic drugs for treating Parkinsons disease (PD). Although several neuroimaging studies have reported altered striatofrontal function that contributes to the emergence of these motor complications, the neuroanatomical correlates of this disorder are still unknown. Optimized voxel‐based morphometry (VBM) was applied to the MRI brain images of 36 PD patients with levodopa‐induced dyskinesias, 36 PD patients without levodopa‐induced dyskinesias, and 32 age‐ and sex‐matched controls. The VBM analysis comparing dyskinetic and nondyskinetic groups provided evidence of increased gray matter volume of the bilateral inferior frontal gyrus in dyskinetic patients, a finding that was more evident in patients with early‐onset PD. No significant differences were detected in the dyskinetic and nondyskinetic groups when compared with the controls. Our findings suggest that the presence of dyskinesias in patients with PD is characterized by an aberrant neural plasticity that could play a role in the pathophysiology of these motor complications.

Voluptuary habits and clinical subtypes of Parkinson's disease: The FRAGAMP case–control study

We evaluated the possible association between smoking, coffee drinking, and alcohol consumption and Parkinsons disease (PD). The FRAGAMP study is a large Italian multicenter case–control study carried out to evaluate the possible role of environmental and genetic factors in PD. Adjusted ORs were estimated using unconditional logistic regression. Smoking, coffee, and alcohol consumption were also considered as surrogate markers of lifestyle and analysis was carried out considering the presence of at least one, two, or three factors. This latter analysis was separately performed considering Tremor‐Dominant (TD) and Akinetic‐Rigid (AR) patients. Four hundred ninety‐two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. Multivariate analysis showed a significant negative association between PD and cigarette smoking (OR 0.51; 95%CI 0.36–0.72), coffee drinking (OR 0.61; 95%CI 0.43–0.87) and wine consumption (OR 0.62; 95%CI 0.44–0.86); a significant trend dose‐effect (P < 0.05) has been found for all the factors studied. We have also found a trend dose‐effect for the presence of at least one, two or three factors with a greater risk reduction (83%) for the presence of three factors. However, a different strength of association between TD and AR was found with a greater risk reduction for the AR patients. We found a significant inverse association between PD smoking, coffee, and alcohol consumption. When analysis was carried out considering the association of these factors as possible surrogate markers of a peculiar lifestyle the association was stronger for the AR phenotype.

Hormonal replacement therapy in women with Parkinson disease and levodopa-induced dyskinesia: a crossover trial.

Eleven postmenopausal women with Parkinson disease and levodopa-induced peak-dose dyskinesias underwent a double-blind, placebo-controlled, crossover study. The active treatment consisted of estrogen replacement therapy for 12 weeks, followed by medroxyprogesterone acetate for 2 weeks. Estrogen replacement therapy-medroxyprogesterone acetate administration significantly improved peak-dose dyskinesia without worsening motor disability, thus suggesting a possible benefit on dyskinesias in postmenopausal women with Parkinson disease.

Myocardial 123I-MIBG scintigraphy for differentiation of Lewy bodies disease from FTD

Clinical distinction between Lewy bodies disease (LBD) and frontotemporal dementia (FTD) is sometimes difficult. Nigrostriatal dopaminergic degeneration occurs in both LBD and FTD, limiting helpfulness of DAT imaging to differentiate these forms of dementia. Several studies have emphasized the usefulness of myocardial scintigraphy with (123)Metaiodobenzylguanidine ((123)I-MIGB) in assessing the sympathetic nerve terminals in LBD demonstrating that cardiac (123)I-MIGB uptake is decreased in patients with this disease. We investigated the role of cardiac (123)I-MIBG scintigraphy in differentiating patients with LBD from those with FTD. Clinical diagnosis of LBD and FTD was determined according to established consensus criteria. Nine patients with LBD (1 possible and 8 probable), 6 patients with FTD, and 16 control subjects were involved in the study. The heart to mediastinum ratio (H/M) of (123)I-MIBG uptake was markedly reduced in all patients with LBD (H/M early: 1.25±0.12; delayed: 1.14±0.13) whereas it was normal in patients with FTD (H/M early: 1.86±0.20; delayed: 1.80±0.23) and in controls (H/M early: 1.91±0.17; delayed: 1.99±0.19), suggesting that cardiac (123)I-MIBG scintigraphy can help distinguish patients with LBD from those with FTD.

The fragile X premutation presenting as postprandial hypotension

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder consisting of progressive intention tremor and cerebellar ataxia recently described in men with the premutation (55 to 200 CGG repeats) in the promoter region of the fragile X mental retardation 1 ( FMR1 ) gene1 and with grandchildren with fragile X syndrome (FXS).2 We describe here a patient with postprandial hypotension and intention tremor carrying an FMR1 premutation allele and without a family history for FXS. A 73-year-old man was referred to our clinic for episodes of blurred vision, dizziness, and weakness appearing after meals and associated with low blood pressure (BP) values. These episodes began 1 year before our visit, but the patient also had bilateral hand tremor with onset at age 71 years, mostly pronounced with posture and action. His family history was unremarkable for peculiar neurologic disorders: he had two healthy sons aged 42 and 39 years and two healthy grandchildren. Moreover, he had only two sisters: one died at age 38 years …

Compound heterozygosity in DJ-1 gene non-coding portion related to parkinsonism.

In this study we analysed the DJ-1 gene in 40 sporadic patients with early onset Parkinsons disease and 100 appropriate controls, originated from southern Italy. We identified a single patient with age at onset of 38 years carrying two previously undescribed heterozygous mutations, both located in non-coding regions. The first mutation was a nucleotide change in the promoter region of the gene (g.159C>G) and the second one was an insertion in the intron 4 splice site (IVS4+3insA). In the same patient, genomic rearrangements were excluded. No DJ-1 mutations were found in the remaining parkinsonian patients. Our results support the growing importance of mutations in non-coding portion of human genome, and confirm that alterations in DJ-1 are a cause, even if rare, of early-onset Parkinsons disease.

HOMER1 Promoter Analysis in Parkinson’s Disease: Association Study with Psychotic Symptoms

Aims:HOMER1 gene expression has been linked to abnormal movements in animals receiving chronic administration of antipsychotics. The continuing neurodegeneration of Parkinson’s disease (PD) and the prolonged use of L-dopa are associated with motor complications, such as dyskinesia, and psychotic side effects, including hallucinations and paranoid delusions. Approximately 25–40% of patients with idiopathic PD experience hallucinations. Genetic variability within different candidate genes has been implicated in the clinical severity of sporadic PD in many populations. Materials and Methods: We investigated 3 polymorphisms located in the 5′ flanking region of the HOMER1 gene within a sample of 131 sporadic PD patients from southern Italy, using a 3-SNP genotype and haplotype combination (rs4704559, rs10942891, rs4704560). Results: Our study implicates the effects of allele A of the rs4704559 marker in susceptibility to psychotic symptoms in PD (χ2 = 8.092, 1 d.f., p = 0.004). Conclusion: Even though our results are preliminary, this HOMER1 gene variant may represent a biomarker for side effect evaluation in PD patients.

FRAXE intermediate alleles are associated with Parkinson’s disease

There is evidence that male subjects with a clinical picture of action tremor, Parkinsonism, and cerebellar ataxia may have Fragile X premutations (FRAXA). We analyzed FRAXA and FRAXE triplet repeats in 203 male subjects with Parkinsons disease (PD) and 370 healthy controls. No full mutations or premutations at the FRAXA and FRAXE loci were found in the subjects with PD or in the controls. FRAXA allele distribution was similar in patients and controls. FRAXE intermediate alleles (31-60 repeats CCG) were found in 13 of 203 (6.4%) subjects with PD and in only one of the 370 (0.27%) healthy controls (P < 0.001), thus indicating that these relatively large alleles may be associated with PD.

Association of tau gene polymorphism with Parkinson's disease.

Abstract.We investigated the segregation of the dinucleotide GT repeat polymorphism in the intron between exons 9 and 10 of the tau gene in 300 patients with Parkinson’s disease (PD) and in 197 normal controls. The A3 allele was more frequent in cases than in controls (30% versus 16%, p<0.001), and individuals carrying at least one A3 allele in their genotype had an increased risk of developing PD (odds ratio 2.78, 95% confidence interval 1.81–4.29). No significant differences were found between patients by considering the age at onset and the presence of family history or dementia. Our findings suggest a possible involvement of the tau gene in the pathogenesis of PD.