Roberta Marchese

Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects

Several clues suggest that α-synuclein, a presynaptic protein, plays a central role in the pathogenesis of idiopathic Parkinsons disease (PD). To search a peripheral marker of PD, we analyzed presence and amount of α-synuclein in CSF from 12 PD patients and 10 neurologically normal subjects. The protein was extracted from CSF samples through immunoprecipitation and immunoblotting with different specific anti-α-synuclein antibodies. We identified a 19 kDa band that corresponds to monomeric α-synuclein, given its comigration with homologue human recombinant peptide as well as with the protein extracted from cerebral cortex of normal subjects. The amount of CSF 19 kDa α-synuclein did not significantly vary in PD and normal cases. These findings have two implications: (a) full length α-synuclein is released by neurons in the extracellular space; (b) α-synuclein does not appear a peripheral marker of PD pathology.

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background. Ann Neurol 2000;47:374–377

Effect of cognitive and motor tasks on postural stability in Parkinson's disease: a posturographic study.

To analyse the effect of concomitant cognitive or motor task performance on balance control in Parkinsons disease (PD), we performed a posturographic study in 24 PD patients and in 20 sex‐ and age‐matched control subjects. Postural sway was measured with eyes open (EO) and eyes closed (EC) during quiet stance and during performance of calculation or motor sequence of thumb opposition to the other fingers. No difference of centre of foot pressure (COP) parameters was observed during quiet standing (either EO or EC) between patients and controls, but visual deprivation induced in both groups a worsening of postural stability. COP area was significantly increased in PD patients during dual task performance, whereas no difference of COP path and x–y axes was observed. The effects induced by the performance of cognitive or motor task were significantly more evident in PD patients with clinical evidence of postural instability (presence of prior falls in the history). This study demonstrates that dual task interference on postural control can be observed in PD patients during performance of cognitive as well as motor tasks. The balance deterioration during dual task performance was significantly enhanced in patients with history of prior falls. These findings have some implications for the strategies to be used in reducing the risk of fall in PD.

Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study

OBJECTIVE To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. DESIGN Case-control study. PATIENTS AND METHODS Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. RESULTS The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. CONCLUSION These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians

It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinsons disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

REM sleep behaviour disorder in Parkinson's disease: a questionnaire-based study

The aim of the study was to determine the clinical frequency and features of REM sleep behaviour disorder (RBD) in a large population of Parkinson’s disease (PD) patients using defined diagnostic criteria both for RBD and PD. Six trained neurologists used a semistructured questionnaire based on ICSD-R diagnostic criteria for RBD to evaluate 200 PD patients and their caregivers. Interobserver reliability for the diagnosis of RBD was “substantial” (Kappa 0.65). Five patients were excluded from the study because of an MMSE lower than 25. The demographic and PD clinical features were compared in the clinically defined RBD group and in those without RBD (NRBD). Then the RBD features during the last year were analysed in the affected group. Out of 195 patients, 66 fulfilled the ICSD-R criteria for RBD; 62 patients reported RBD during the last year (frequency 31.8%). RBD features: two or more episodes per week in 35.5%; upper limb movements in 87%; lower limb movements in 79%; vocalisations during events in 85%. RBD onset was before PD in 27% of patients; 69% of the RBD group had injured themselves or their caregivers during sleep. According to multivariate analysis, RBD was associated with male gender, age and PD duration. Brief training and the use of a semistructured questionnaire may help the neurologist in dealing with sleep disturbances in PD patients. The search for RBD symptoms in PD is highly recommended, especially in patients with a long disease duration, the risk of sleep-related injuries being high.

The role of sensory cues in the rehabilitation of parkinsonian patients : A comparison of two physical therapy protocols

We devised a single‐blind study to assess the role of providing external sensory cues in the rehabilitation of patients with idiopathic Parkinsons disease (PD). Twenty stable, nondemented patients with PD entered a 6‐week rehabilitation program and were randomly assigned to two balanced protocols which were differentiated by the use of external sensory cues (“non‐cued” vs “cued”). Patients were evaluated by a neurologist, who was blind to group membership, with the Unified Parkinsons Disease Rating Scale (UPDRS) at baseline, end of treatment, and after 6 weeks. Patient groups were comparable for age, disease duration, and severity. A significant reduction of UPDRS scores (activities of daily living and motor sections) was present after the rehabilitation phase in both groups. However, at follow up, while this clinical improvement had largely faded in the “non‐cued” group, mean UPDRS scores of the “cued” group were still significantly lower than baseline values. The incorporation of external sensory cues in the rehabilitation protocol can extend the short‐term benefit of physical therapy in moderately disabled patients with PD, possibly as a result of the learning of new motor strategies. “Cued” physical therapy for PD should be targeted to compensate for the defective physiological mechanisms.

Motor recovery following stroke: a transcranial magnetic stimulation study

OBJECTIVES To verify the usefulness of early recording of motor evoked potentials (MEPs) in predicting motor outcome after stroke and to investigate the neural mechanisms underlying functional recovery following stroke. METHODS We performed a comparative analysis of the behaviour of motor responses evoked by transcranial magnetic stimulation (TMS) of the ipsilateral and contralateral motor cortex in the affected and unaffected thenar muscles of 21 consecutive patients with acute stroke. RESULTS According to the behaviour of MEPs in the affected muscles, patients could be divided into 3 groups: (a) 10 subjects with absent responses to TMS of both the damaged and undamaged hemisphere, whose motor recovery was poor and related to the size of MEPs on the normal side; (b) 5 subjects with larger MEPs upon TMS of the ipsilateral (undamaged) than of the contralateral (damaged) cortex, whose good recovery possibly resulted from the emergence of ipsilateral pathways; (c) 6 subjects with larger MEPs in the affected than in the unaffected muscles, whose good recovery was possibly subserved by alternative circuits taking over cortical deafferentation. CONCLUSIONS Early MEP recording in acute stroke provides useful information on the clinical prognosis and the different mechanisms of motor recovery.

PINK1 , Parkin , and DJ-1 mutations in Italian patients with early-onset parkinsonism

Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2±5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinsons disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2±9.7 (range 25–49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (−21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.

Changes of intracortical inhibition during motor imagery in human subjects.

Paired-pulse transcranial magnetic stimulation with a conditioning-test paradigm was used to assess changes of corticocortical inhibition and facilitation during mental simulation of sequential finger movements in normal subjects. The cortico-cortical inhibition (at interstimulus interval, ISI, of 3 ms) was significantly reduced in the relaxed opponens pollicis (OP) muscle during motor imagery, regardless of the absolute size of the test motor evoked potential. The amount of cortico-cortical inhibition was similar to that observed during a mild voluntary contraction of the OP. No change of cortico-cortical facilitation was observed at the ISI of 12 ms. The data support the hypothesis that similar neural structures, including the primary motor cortex, are activated during both mental simulation and actual execution of motor activities.