Livia Brusa

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.

Frontal lobe dysfunction in essential tremor: a preliminary study.

Abstract 27 patients with essential tremor (ET) were studied to determine the cognitive feature of this condition. 15 familial cases and 12 cases with a family history Parkinsons disease (PD) were identified. Performances on frontal lobe tasks of ET patients were compared with those of 15 patients with PD and 15 healthy control subjects. The ET patients showed significant impairments both in attentional and conceptual thinking tasks, similar to those observed in the PD group. Despite the nosographic independence of the two conditions, data showed that the frontal lobe feature of ET was similar to those of PD, thus possibly suggesting a common dysregulation of dopamine pathways.

Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease

Background: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis. Methods: In a series of experiments, we applied repetitive transcranial magnetic stimulation (rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, to investigate whether modulation of cerebellothalamocortical circuits by means of rTMS may result in a modification of a dyskinetic state induced by levodopa ingestion. Results: We found that a single session of cerebellar continuous theta burst stimulation (cTBS) was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBS changed the profile of activation of intracortical circuits in the contralateral primary motor cortex. Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition, inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in another experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persistent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the daily stimulation period. Conclusions: Our study demonstrates that cerebellar continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possibly due to modulation of cerebellothalamocortical pathways.

rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease

The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.

Subthalamic stimulation activates internal pallidus: Evidence from cGMP microdialysis in PD patients

Parkinsons disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN‐DBS. This supports the view that a clinically beneficial effect of STN‐DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi. Ann Neurol 2005;57:448–452

Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations

Objective: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. Methods: In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. Results: Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged “on-time” duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. Conclusions: These data demonstrate a reversible Helicobacter pylori (HP)–induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.

Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis

Objective: To investigate whether repetitive transcranial magnetic stimulation (rTMS) can modify spasticity. Methods: We used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing–remitting multiple sclerosis and lower limb spasticity. Results: A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased corticospinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when the patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. Conclusions: Repetitive transcranial magnetic stimulation may improve spasticity in multiple sclerosis.

Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson's disease.

Summary.Quantifications of Al, Ca, Cu, Fe, Mg, Mn, Si and Zn were performed in urine, serum, blood and cerebrospinal fluid (CSF) of 26 patients affected by Parkinson’s disease (PD) and 13 age-matched controls to ascertain the potential role of biological fluids as markers for this pathology. Analyses were performed by Inductively Coupled Plasma Atomic Emission Spectrometry and Sector Field Inductively Coupled Plasma Mass Spectrometry. The serum oxidant status (SOS) and anti-oxidant capacity (SAC) were also determined. Results showed a decreasing trend for Al in all the fluids of PD patients, with the strongest evidence in serum. Calcium levels in urine, serum and blood of PD patients were significantly higher than in controls. Copper and Mg concentrations were significantly lower in serum of PD patients. Levels of Fe in urine, blood and CSF of patients and controls were dissimilar, with an increase in the first two matrices and a decrease in CSF. No significant difference was found in levels of Mn between patients and controls. Urinary excretion of Si was significantly higher in PD subjects than in controls. No clear difference between Zn levels in the two groups was found for serum, urine or CSF, but an increase in Zn levels in the blood of PD patients was observed. The SOS level in PD was significantly higher while the corresponding SAC was found to be lower in patients than in controls, in line with the hypothesis that oxidative damage is a key factor in the pathogenesis of PD. The results on the whole indicate the involvement of Fe and Zn (increased concentration in blood) as well as of Cu (decreased serum level) in PD. The augmented levels of Ca and Mg in the fluids and of Si in urine of patients may suggest an involuntary intake of these elements during therapy.

Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains

Between 2005 and 2007, six patients affected by idiopathic Parkinsons disease (IPD) were submitted to the bilateral implantation (and subsequent deep brain stimulation - DBS) of the pedunculopontine nucleus (PPN) plus the subthalamic nucleus (STN). This review synthesizes the effects of PPN low-frequency stimulation on non-motor functions, focusing on patient sleep quality and cognitive performance. If not associated to STN-DBS, PPN-DBS promoted a modest amelioration of patient motor performance. However, during PPN-DBS, they experienced on the one hand a significant improvement in executive functions and working memory, on the other hand a beneficial change in sleep architecture. Overall, the limited sample hampers definite conclusions. Yet, although the PPN-DBS induced motor effects are quite disappointing (discouraging extended trials based upon the sole PPN implantation), the neuropsychological profile supports the contention by which in selected PD patients, with subtle cognitive deficits or vanished efficacy of previous implanted STN, PPN-DBS might still represent a reliable and compassionate option.

Low frequency rTMS of the SMA transiently ameliorates peak-dose LID in Parkinson’s disease

OBJECTIVE To determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) may modulate l-DOPA-induced dyskinesia (LID) in dyskinetic Parkinsons disease (PD) patients. LID is a severe motor complication in advanced PD patients. The neural mechanisms involved in LID are not clear, and it is apparent that both an excessive decrease in internal pallidus firing and a modification and overactivation of cortical motor and premotor areas are involved in its pathogenesis. METHODS Using low frequency 1Hz repetitive rTMS we investigated whether decrease of excitability of the supplementary motor area (SMA) may result in modification of LID in PD patients. Furthermore we tested whether it was possible to enhance and/or prolong the beneficial effects of the treatment with repeated sessions of stimulation. RESULTS We observed that 1Hz rTMS induced a transient reduction of dyskinesias. A single session of rTMS improved LID, while repeated sessions of stimulation failed to enhance and/or prolong the beneficial effects of the procedure, without causing motor deterioration or other adverse effects. CONCLUSIONS These results suggest that LID may depend on an increased excitability of the SMA. SIGNIFICANCE SMA rTMS is effective in reducing transiently LID, although cannot yet be considered clinically useful.