PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum.

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

GPi-DBS in Huntington's disease: results on motor function and cognition in a 72-year-old case.

Huntington's disease (HD) produces debilitating motor abnormalities that are poorly responsive to medical therapy. Deep brain stimulation (DBS) of the posteroventral globus pallidus internus (GPi) may offer a treatment option for patients with diskinetic phenotype and minimal cognitive impairment, but its role in the management of HD remains unclear and to date only two cases have been reported. We report the outcome of GPi-DBS in a 72-year-old man with HD. Stimulation at 130 Hz caused a rapid amelioration of chorea producing the worsening of bradykinesia, whereas 40 Hz stimulation (maintaining constant the total electrical energy delivered) improved chorea while preserving the ability to walk. At 1-year follow-up, chorea has completely disappeared; however, the patient was unable to stand and walk. The cognitive profile showed a progressive deterioration, with an extension of deficit from the mainly dysexecutive alterations at baseline to a more diffused cognitive deterioration.

Effects of stimulation of the subthalamic nucleus on naming and reading nouns and verbs in Parkinson's disease.

UNLABELLED: An impairment for verbs has been described in patients with Parkinson's disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation may affect the ability to select from many competing lexical alternatives. In this study, 12 PD patients who had undergone bilateral STN DBS and completed an 8-year follow-up and 14 matched normal controls were administered action and object naming tasks and verb and noun reading tasks. Their responses were recorded using a microphone, resulting in a signal that marked the onset of the verbal response and allowed to measure response times (RTs). Accuracy was scored manually. RESULTS: Overall performance in naming (independently of stimulation): In naming task controls were faster and more accurate than PD patients. In both groups, performance (accuracy and RTs) was worse on action naming than object naming. PD patients were significantly slower than controls in naming actions. Effect of stimulation: Compared with the OFF stimulation condition, in ON stimulation condition PD patients showed improved performance on object and action naming tasks (increased accuracy, faster RTs), with a decreased number of semantic errors. Some evidence also emerged that action naming in the ON stimulation condition improved more than object naming. On noun and verb reading tasks, although accuracy was at ceiling in both groups and no significant difference was observed in RTs for nouns and verbs, PD patients were slower than controls. CONCLUSIONS: Our findings suggest that STN DBS may improve lexical search in PD patients. We hypothesize that STN stimulation may facilitate the motor components involved in naming and reading tasks (increased speed of speech onset), resulting in shorter RTs in both naming and reading and, to some extent, in increased accuracy in naming due to fewer omissions (no response within the 7500 ms time limit). However, to account for greater accuracy in naming due to decreased number of semantic errors in the ON stimulation condition, we hypothesize that STN stimulation restores the activity of the corticostriatal circuits involved in selection processes of a target word among different alternatives.

Unilateral extradural motor cortex stimulation is safe and improves Parkinson disease at 1 year.

BACKGROUND: The primary motor cortex, which is part of the corticobasal ganglia loops, may be an alternative option for the surgical treatment of Parkinson disease. OBJECTIVE: To report on the 1-year safety and efficacy of unilateral extradural motor cortex stimulation in Parkinson disease. METHODS: A quadripolar electrode strip was extradurally implanted over the motor cortex. Stimulation was continuously delivered through the electrode paddle contralateral to the most affected clinical side. Subjects were prospectively evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson's Disease Quality of Life Questionnaire. In addition, an extensive cognitive and behavioral assessment and electroencephalogram recording were performed. RESULTS: Nine patients were included in this study. No surgical complications or adverse events occurred. Moreover, no cognitive or behavioral changes were observed. Under the off-medication condition, the UPDRS III at baseline was decreased by 14.1%, 23.3%, 19.9%, and 13.2%, at 1, 3, 6, and 12 months, respectively. The motor effects were bilateral, appeared after 3 to 4 weeks of stimulation, and outlasted the stimulation itself for 3 to 4 weeks in 1 case of stimulator accidental switching off. The UPDRS IV was decreased by 40.8%, 42.1%, and 35.5% at 1, 3, and 12 months, respectively. The scores on the Parkinson's Disease Quality of Life Questionnaire were increased at months 3, 6, and 12. CONCLUSION: Extradural motor cortex stimulation is a safe procedure. After 12 months, the patients demonstrated a moderate improvement of motor symptoms (particularly axial symptoms) and quality of life.

Chronic motor cortex stimulation in patients with advanced Parkinson's disease and effects on striatal dopaminergic transmission as assessed by 123I-FP-CIT SPECT: a preliminary report.

OBJECTIVE: The objective of this study was to assess striatal dopamine transporter availability in patients with advanced Parkinson's disease (PD) before and after 13 months of unilateral extradural motor cortex stimulation (EMCS) with [123I]N-ω-fluoropropyl-2-ß-carbo-methoxy-3-ß-(4-iodophenyl)nortropane single photon emission computed tomography (123I-FP-CIT SPECT). METHODS: Six PD patients (five women and one man, aged 63.2 ± 5.6 years) underwent 123I-FP-CIT SPECT and clinical evaluation [Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Quality of Life Scale (PDQL)] preoperatively, 8 and 13 months after EMCS. Striatum-to-occipital cortex, caudate-to-occipital cortex and putamen-to-occipital cortex 123I-FP-CIT uptake ratios were calculated using the region of interest method. RESULTS: Total and part III UPDRS scores significantly decreased at 8 and 13 months after stimulation (P=0.02 and 0.04, respectively); UPDRS part II and PDQL scores improved after 13 months (P=0.02 and 0.04, respectively). No significant differences in 123I-FP-CIT uptake ratios between baseline and follow-up were found in the examined regions. However, a progressive reduction in 123I-FP-CIT uptake ratios in the striatum contralateral to the implant was found. In contrast, no further decrease in 123I-FP-CIT uptake ratios was detected in the striatum ipsilateral to the implant. There were no correlations between changes in 123I-FP-CIT uptake ratios with disease duration, changes in medication dosage and motor UPDRS scores. CONCLUSION: Despite a small but highly selected sample of advanced PD patients, our results showed that no further dopamine transporter reduction occurred in the striatum ipsilateral to the implant side. This finding could lead to the hypothesis that EMCS might elicit a 'neuroprotective' effect, as suggested by significant clinical benefits.

The long-term effect of tetrabenazine in the management of Huntington disease.

OBJECTIVES: To enhance the knowledge on the long-term efficacy and safety of tetrabenazine (TBZ) in managing chorea. METHODS: We analyzed 68 Huntington disease patients (mean disease duration, 55.8 +/- 34.7 months) who had been treated with TBZ for a mean period of 34.4 +/- 25.2 months (median, 34 months; mode, 48 months; range, 3-104 months). We measured the variation from pretreatment of the motor score of Unified Huntington's Disease Rating Scale at the first follow-up visit and at the latest. RESULTS: Mean Unified Huntington's Disease Rating Scale-chorea underscore at the time of the pretreatment visit was 10.4 +/- 4.1 (range, 0-28). At the first follow-up, 9.7 +/- 7.8 months after the prescription of TBZ (mean dose, 35.3 +/- 14.7 mg), mean score of chorea was 8.2 +/- 4.1 (-21% compared with baseline), whereas at the latest follow-up visit (mean dose, 57.5 +/- 14.7 mg), it was 9.5 +/- 5.0 (9%). During the follow-up, the clinical benefit persisted, but the magnitude was reduced despite a progressive increase of the doses (up to 60%). Motor improvement was not influenced by sex, or doses or duration of therapy; age at onset was the only predictor of a good outcome. Five patients (7%) did not gain any improvement, and TBZ was discontinued. There were 2 withdrawals because of side effects; 34 patients reported at least 1 side effect. CONCLUSIONS: Tetrabenazine was well tolerated and produced long-term improvement of motor symptoms in Huntington disease patients, although a slight reduction of benefit occurred during the course of treatment.

Punding and computer addiction in Parkinson's disease.

Punding is a stereotypical behavior in which there is an intense fascination with repetitive handling and examining of mechanical objects, such as taking apart watches and radios or arranging common objects (lining up pebbles, rocks, or other small objects). This disabling condition, different from both obsessive-compulsive disorder and mania, is probably underreported. Punding is thought to be related to dopaminergic stimulation, although only a few observations of this condition in patients with Parkinson's disease (PD) under therapy has been reported. We report a man with PD who developed an unusual, severe, repetitive behavior characterized by spending most of his time on his computer; this abnormal behavior was concomitant with the introduction of L-dopa (400 mg per day) and was not associated to a pattern of chronic inappropriate overuse of dopaminergic medication or other psychiatric symptoms. The patient had the feeling he was forced into a disruptive and unproductive behavior, and he made several attempts to quit without succeeding.

Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson's disease.

To evaluate the frequency of the LRRK2 G2019S mutation in Italy, we tested 1,072 probands with Parkinson's disease (PD; 822 sporadic and 250 familial): 20 patients (1.9%) carried the G2019S mutation, 11 patients (1.3%) were sporadic, and 9 (4.3%) had a positive family history. Considering only probands with autosomal dominant inheritance, the G2019S frequency raises to 5.2%. All presented a typical phenotype with variable onset and shared the common ancestral haplotype. Mutation frequency raised from 1.2% in early onset PD to 4.0% in late onset PD.