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Traditional dogma regarding the brain as an immune exempt organ has changed in recent years. New research has highlighted the role of the classical complement cascade in both synaptic elimination and function, driven largely by the role of the pathway initiating protein C1q. Given the links between C1q and cognitive function we assessed the genetic variability of the C1q encoding genes: C1QA, C1QB and C1QC between PD patients and matched controls. Despite a strong link between C1Q/cognitive decline and PD/cognitive decline we were unable to find a link between common C1Q variation and PD. We conclude that common C1Q-A/B/C genetic variation is unlikely to contribute to cognitive decline or the missing heritability in PD., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Although the short-term benefits of posteroventral pallidotomy for patients with advanced Parkinson's disease have been well documented, little is known about the long-term outcome of the procedure., Methods: We conducted a long-term follow-up study of a cohort of 40 patients who had undergone unilateral posteroventral medial pallidotomy between 1993 and 1996. Twenty patients were not evaluated because they had undergone a second surgical procedure (11 patients) or had died (2) or because they had dementia or another debilitating illness (4), lived too far away (1), or had been lost to follow-up (2). We conducted serial postoperative assessments of parkinsonism in the remaining 20 patients while they were taking medications ("on" period) and after overnight withdrawal of the drugs ("off" period). The mean follow-up time was 52 months (range, 41 to 64)., Results: The combined off-period score for activities of daily living and motor function on the Unified Parkinson's Disease Rating Scale was 18.0 percent better at the last evaluation than at base line (95 percent confidence interval, 4.9 to 31.0 percent; P=0.01). Significant improvements were also evident in the off-period scores for contralateral tremor (65.4 percent improvement, P=0.007), rigidity (43.2 percent, P=0.03), and bradykinesia (18.2 percent, P=0.04) and in the on-period score for contralateral dyskinesia (70.6 percent, P<0.001). Changes in medication did not contribute to the sustained improvement. The 20 patients who could not be included in the long-term analysis had similar base-line characteristics but a worse response to surgery at six months., Conclusions: In the group of patients with advanced Parkinson's disease who could be enrolled in our long-term follow-up study of unilateral posteroventral medial pallidotomy (20 patients from the original cohort of 40), significant early improvements in off-period contralateral signs of parkinsonism were sustained for up to five and a half years. There was a sustained significant improvement in on-period contralateral dyskinesia but not in other on-period signs of parkinsonism.

There has been a resurgence in the use of functional neurosurgery for Parkinson's disease. An important factor that has played a role in this development is the recent understanding of the functional anatomy of the basal ganglia including a knowledge of the changes in the activities of neurons in the internal segment of the globus pallidus (Gpi) and the subthalamic nucleus (STN) in Parkinson's disease as well as the knowledge of the presence of segregated functional loops within the basal ganglia which include a sensory-motor loop that involves the posteromedial globus pallidus rather than the anterior GPi where earlier pallidotomy lesions had been made. Laitinen reintroduced the modern posteroventral medial pallidotomy (PVMP) in 1992. Since then it has become clear that this treatment has major effects on levodopa-induced dyskinesias and, unlike Vim thalamotomy, improves bradykinesia and rigidity as well as tremor. In this report, we review a number of topics related to PVMP including the clinical results of pallidotomy available in the literature as well as an update of our own 2 year follow-up data, studies evaluating factors that might predict the subsequent response to pallidotomy, the neuropsychological effects of the procedure, results of imaging studies including the correlation of clinical effects with lesion location, the question of bilateral pallidotomy and pallidotomy combined with deep brain stimulation and finally whether PVMP is effective in other parkinsonian disorders.

The purpose of this study was to examine the relationship between lesion location and clinical outcome following globus pallidus internus (GPi) pallidotomy for advanced Parkinson's disease. Thirty-three patients were prospectively studied with extensive neurological examinations before and at 6 and 12 months following microelectrode-guided pallidotomy. Lesion location was characterized using volumetric MRI. The position of lesions within the posteroventral region of the GPi was measured, from anteromedial to posterolateral along an axis parallel to the internal capsule. To relate lesion position to clinical outcome, hierarchical multiple regression analysis was used. The variance in outcome measures that was related to preoperative scores and lesion volume was first calculated, and then the remaining variance attributable to lesion location was determined. Lesion location along the anteromedial-to-posterolateral axis within the GPi influenced the variance in total score on the Unified Parkinson's Disease Rating Scale in the postoperative 'off' period, and in 'on' period dyskinesia scores. Within the posteroventral GPi, anteromedial lesions were associated with greater improvement in 'off' period contralateral rigidity and 'on' period dyskinesia, whereas more centrally located lesions correlated with better postoperative scores of contralateral akinesia and postural instability/gait disturbance. Improvement in contralateral tremor was weakly related to lesion location, being greater with posterolateral lesions. We conclude that improvement in specific motor signs in Parkinson's disease following pallidotomy is related to lesion position within the posteroventral GPi. These findings are consistent with the known segregated but parallel organization of specific motor circuits in the basal ganglia, and may explain the variability in clinical outcome after pallidotomy and therefore have important therapeutic implications.

Objective: To evaluate, in a double-blind fashion, the efficacy of deep brain stimulation of the internal segment of the globus pallidus (GPi) contralateral to a previous unilateral medial pallidotomy (MP)., Methods: This pilot study involved 4 patients with a previous MP and one previously unoperated patient unable to tolerate any antiparkinsonian drugs. One of the patients with a prior unilateral MP had two electrodes implanted in the contralateral side, one in GPi and one in Vim thalamus. Detailed neurologic assessments were performed after overnight drug withdrawal and in the drug "on" state at baseline, 1 week and 3 months (in all), and 9 and 12 months (one) with patients and evaluators blinded to the status of stimulation., Results: GPi stimulation resulted in improvements in "off-period" contralateral bradykinesia, rigidity and tremor in all patients. Dyskinesias and freezing episodes were ameliorated in one patient each but dyskinesias were transiently induced in another. The patient with GPi + Vim electrodes had complete resolution of contralateral tremor with thalamic stimulation but less benefit from acute GPi stimulation. One patient experienced a single seizure one week post-op and no other surgical complications were observed., Conclusions: Deep brain stimulation can be applied safely and effectively in patients who have already had a pallidotomy on the contralateral side. The effect of stimulation at different sites on different symptom profiles and levodopa-induced dyskinesias requires further evaluation.

The objective of this study was to examine the experience of spouses caregiving for their spouse with Parkinson's disease (PD) and to determine whether their experiences differed by stage of disease. By using a cross-sectional design and mail questionnaire data from 380 spouse caregivers across 23 sites of the Parkinson Study Group, key caregiver variables were examined by stage of PD. Three categories of variables--caregiver role strain (10 measures), caregiver situation (four measures), and caregiver characteristics (four measures)--were analyzed by using t tests with Bonferroni correction. Specific types and amounts of role strain accumulated as the disease progressed, and they differed significantly between stages (p < 0.05). In the caregiving situation, the mean number of caregiving tasks tripled by stage 4/5. Negative changes in lifestyle plus decreases in predictability in caregivers' lives increased significantly in late-stage disease (p < 0.05). Caregiver characteristics of physical health and preparedness did not significantly differ across stages of disease. Depression was significantly higher by stage 4/5. Mutuality, the positive quality of the relationship as perceived by the caregiving spouse, declined beginning at stage 2. Caregiver strain is experienced across all stages of PD and accumulates significantly as the disease progresses. This study defines types and amounts of strain by stage of disease, which will be helpful in designing formal intervention trials to provide more effective help for spouse caregivers.

Background: Posteroventral medial pallidotomy sometimes produces striking improvement in patients with advanced Parkinson's disease, but the studies to date have involved small numbers of patients and short-term follow-up., Methods: Forty patients with Parkinson's disease underwent serial, detailed assessments both after drug withdrawal ("off" period) and while taking their optimal medical regimens ("on" period). All patients were examined preoperatively and 39 were examined at six months; 27 of the patients were also examined at one year, and 11 at two years., Results: The percent improvements at six months were as follows: off-period score for overall motor function, 28 percent (95 percent confidence interval, 19 to 38 percent), with most of the improvement in the contralateral limbs; off-period score for activities of daily living, 29 percent (95 percent confidence interval, 19 to 39 percent); on-period score for contralateral dyskinesias, 82 percent (95 percent confidence interval, 72 to 91 percent); and on-period score for ipsilateral dyskinesias, 44 percent (95 percent confidence interval, 29 to 59 percent). The improvements in dyskinesias and the total scores for off-period parkinsonism, contralateral bradykinesia, and rigidity were sustained in the 11 patients examined at two years. The improvement in ipsilateral dyskinesias was lost after one year, and the improvements in postural stability and gait lasted only three to six months. Approximately half the patients who had been dependent on assistance in activities of daily living in the off period before surgery became independent after surgery. The complications of surgery were generally well tolerated, and there were no significant changes in the use of medication., Conclusions: In late-stage Parkinson's disease, pallidotomy significantly reduces levodopa-induced dyskinesias and off-period disability. Much of the benefit is sustained at two years, although some improvements, such as those on the ipsilateral side and in axial symptoms, wane within the first year. The on-period symptoms that are resistant to dopaminergic therapy do not respond to pallidotomy.

Surgical treatments for PD and ET are promising. Medial Pallidotomy, the surgical lesioning of the pallidum, often improves symptoms of long-standing PD. We enrolled twenty-seven late stage PD patients for unilateral medial pallidotomy who were then assessed by the Core Assessment Program for Intracranial Transplantation (CAPIT) protocol. One year after surgery persistent improvement was seen contralateral to the lesion in the following features: drug-induced dyskinesias (92%), akinesia (38%), rigidity (51%), and tremor (42%). Complications included transient dysarthria (7 patients), facial weakness (9 patients), limb weakness (1 patient), swallowing problems (4 patients) and intracerebral haemorrhage (1 patient). Thalamic DBS may improve tremor in PD and ET patients. Therefore, we enrolled fifteen patients (9 PD and 6 ET patients) with disabling tremor, unresponsive to medication. They were assessed by the United Parkinson's Disease Rating Scale (UPDRS) and the Tremor Rating Scale (for PD and ET patients, respectively). Three months after surgery, limb tremor contralateral to stimulation improved by 71% in PD patients and 76% in ET patients. Complications included transient paresthesias (all), confusional state (1 patient) and intracerebral bleed (1 patient). Unilateral medial pallidotomy safely improves some Parkinsonian symptoms contralateral to the lesion. Thalamic DBS may effectively and safely improve contralateral limb tremor in PD and ET.

Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system characterized by tremor, rigidity, slowness of movement (bradykinesia) and postural abnormalities. The cause is unknown, but the pathology shows that dopamine is profoundly reduced in the basal ganglia of patients with PD. When dopamine is replenished by the administration of levodopa, most of the symptoms of parkinsonism are reduced significantly. Levodopa is considered to be the most reliable and effective symptomatic drug treatment for keeping patients autonomous and functionally independent for as long as possible.

The major motor disturbances in Parkinson's disease are thought to be caused by overactivity of the internal segment of the globus pallidus (GPi), in large part due to excessive drive from the subthalamic nucleus. The excessive inhibitory activity of GPi is thought to "brake' the motor thalamus and the cortical motor system to produce the slowness, rigidity, and poverty of movement characteristic of parkinsonian states. To test the hypothesis that direct reduction of Gpi activity can improve motor function, we studied the effect of GPi pallidotomy in 14 patients. The location of the GPi nucleus was confirmed by microelectrode recording before lesion creation. Standardised videotape recordings before and after operation were randomised and scored by a "blinded' evaluator. 6 months after surgery, total motor score in the "off" state had improved by 30% and the total akinesia score by 33%. The gait score in the "off" state improved by 15% and a composite postural instability and gait score by 23%. After surgery there was almost total elimination of drug-induced involuntary movements (dyskinesias), with a 92% reduction on the side contralateral to the pallidotomy. No patient had visual or corticospinal complications. In these patients GPi pallidotomy enhanced motor performance, reduced akinesia, improved gait, and eliminated the neural elements responsible for levodopa-induced dyskinesias.

Remoxipride is a novel substituted benzamide that more effectively blocks mesolimbic than striatal D2 dopamine receptors. We used remoxipride in the management of nine patients with Parkinson's disease (PD) who were experiencing visual hallucinations due to dopaminergic therapy. Remoxipride was begun in a dose of 25 mg three times daily and gradually increased to 75-225 mg/d (mean 161 mg). The psychiatric status improved in eight patients. Little or no change in the severity of parkinsonism was noted in five, a mild increase in two, and a moderate increase in two. Because one patient with moderately severe levodopa-induced dyskinesias experienced a reduction in the abnormal movements without a substantial increase in parkinsonism, we began a trial of remoxipride for disabling peak-dose dyskinesias. The trial was abandoned after every one of the first four patients entered experienced an immediate, severe, and prolonged increase in off periods with single 10- to 25-mg doses. This striking differential response to an atypical neuroleptic with weak striatal D2 antagonist properties indicates that different states of postsynaptic dopamine receptor sensitivity or synaptic dopamine levels may be associated with various disease- and treatment-related problems found in late-stage PD.