Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD

Abstract Objective To compare the cognitive and behavioural effects of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation. Methods After baseline examination 34 patients were randomly assigned to unilateral pallidotomy (4 left-sided, 10 right-sided) or bilateral STN stimulation (n=20). At baseline and six and twelve months after surgery we administered neuropsychological tests of language, memory, visuospatial function, mental speed and executive functions. Also a depression rating scale, and self and proxy ratings of memory and dysexecutive symptoms were administered. Results Six months after surgery, the STN group and the pallidotomy group differed significantly in change from baseline in number of errors on two tests of executive functioning. After 12 months the STN group reported less positive affect compared with baseline than the pallidotomy group. One patient in the STN group showed an overall cognitive deterioration due to complications. Conclusions Although we need larger groups to draw firm conclusions, our results suggest that bilateral STN stimulation has slightly more negative effects on executive functioning than unilateral pallidotomy.     

Effects of pallidotomy and bilateral subthalamic stimulation on cognitive function in Parkinson disease

Unilateral pallidotomy and bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinsons disease (PD) have demonstrated a positive effect on motor functions. However, further studies are needed of the unintended cognitive effects accompanying these new surgical procedures. We studied the consequences of unilateral pallidotomy and STN-DBS on cognitive function in a controlled comparative design. Sixteen consecutive PD patients were assessed before and 6 months after unilateral pallidotomy (n = 8) and bilateral STN-DBS (n = 8). The same assessments were performed in a control group of eight non-operated matched PD patients recruited from surgery candidates who refused operation. The neuropsychological battery consisted of test measuring memory, attention, arithmetic, problem solving and language, as well as visuospatial, executive and premotor functions. An analysis of variance (factors time and treatment) was applied. No statistically significant differences were found in the presurgical evaluation of clinical and demographic data for the three treatment groups. The controlled comparison between presurgical and postsurgical performance revealed no significant changes in the cognitive domains tested in the pallidotomy group. The STN-DBS group showed a selective significant worsening of semantic verbal fluency (p = 0.005). This controlled comparative study suggests that neither unilateral pallidotomy nor bilateral STN-DBS have global adverse cognitive consequences, but bilateral STN-DBS may cause a selective decrease in verbal fluency.     

Effects of bilateral subthalamic stimulation on sleep in Parkinson’s disease

Abstract.Objective: Sleep disturbances are frequently observed in Parkinsons disease (PD). Bilateral chronic subthalamic nucleus (STN) stimulation is an alternative treatment for advanced PD. Improvements in motor disturbances after STN stimulation are well documented and seem to be associated with better sleep quality, even though the objective effect on sleep structure remains unclear. We have therefore studied the sleep/wakefulness cycle before and after surgical treatment in 10 consecutive parkinsonian patients.Methods: Subjective sleep quality and sleep recordings were evaluated one month before and three months after initiation of STN stimulation. After surgery, the recordings were performed under two conditions: with stimulation (the on condition) and—if patients had given their consent—in the absence of stimulation (the off condition).Results: With STN stimulation, subjective and objective sleep qualities were improved. Total sleep time, sleep efficiency and the durations of deep slow wave sleep and paradoxical sleep increased significantly. When stimulation was absent, sleep disturbances were similar to those observed before surgery.Conclusion: Chronic STN stimulation is associated with a sleep improvement, which can be explained in part by the concomitant decrease in motor disturbances but also by the reduction in dosages of antiparkinsonian medication. However, we can not exclude a direct effect of STN stimulation on sleep regulatory centres.     

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson’s disease

Abstract. Context: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. Objective: To determine in Parkinsons disease (PD) patients using positron emission tomography (PET) and [¹¹C]-Raclopride, whether STN stimulation induces a striatal DA release. Methods: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [¹¹C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [¹¹C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. Results: For PD patients, the mean [¹¹C]-Raclopride BP (± SD) were, in Off stimulation condition: 1.7 ± 0.3 for the right caudate nucleus, 1.8 ± 0.4 for the left caudate nucleus, 2.6 ± 0.5 for the right putamenand 2.6 ± 0.5 for the left putamen. In On stimulation condition: 1.7 ± 0.4 for the right caudate nucleus, 1.9 ± 0.5 for the left caudate nucleus, 2.8 ± 0.7 for the right putamen and 2.7 ± 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. Conclusion: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [¹¹C]-Raclopride.     

Ginsenosides Rb1 and Rg1 effects on survival and neurite growth of MPP<Superscript>+</Superscript>-affected mesencephalic dopaminergic cells

Summary. Ginsenosides Rb1 and Rg1 are the main active ingredients of Panax ginseng C.A. Meyer (Araliaceae). They appear to exert protection against ischaemia and anoxic damage in animal models, suggesting an antioxidative and cytoprotective role. In our study, primary cultures from embryonic mouse mesencephalon are applied to examine the effects of these two ginsenosides on neuritic growth of dopaminergic cells and their survival affected by 1-methyl-4-phenylpyridinium-iodide (MPP⁺). Ginsenoside Rb1 (at 10µM) enhanced the survival of dopaminergic neurons by 19% compared to untreated control. MPP⁺ (at 1µM) significantly reduced the number of dopaminergic neurons and severely affected neuronal processes. Both ginsenosides counteracted these degenerations and significantly protected lengths and numbers of neurites of TH⁺ cells. Both compounds however could not prevent the cell loss caused by MPP⁺. Our study thus indicates partial neurotrophic and neuroprotective actions of ginsenosides Rb1 and Rg1 in dopaminergic cell culture.     

<Emphasis Type="Italic">c</Emphasis><Emphasis Type="Italic">-MYC</Emphasis> amplification and expression in astrocytic tumors

Point mutations and genomic multiplications in the α-synuclein (αSYN) gene cause autosomal-dominant Parkinson’s disease. Moreover, αSYN fibrils are the major component of Lewy bodies, the neuropathological hallmarks of Parkinson’s disease and dementia with Lewy bodies as well as of glial cytoplasmic inclusions in multiple system atrophy. These diseases are collectively referred to as α-synucleinopathies. Cellular mechanisms regulating αSYN fibril formation and toxicity are intensely studied in vitro, and in cell culture and diverse animal models. Specific neuropathology was achieved in transgenic mouse models using several promoters to express human wild-type and mutant αSYN in brain regions affected by the various α-synucleinopathies. Somatodendritic accumulation of the transgenic αSYN with neuritic distortions was a common finding. The nigrostriatal dopaminergic projections were surprisingly resistant to α-synucleinopathy in transgenic mice, although they tended to be more vulnerable to neurotoxins. In a few mouse models, αSYN aggregated in an age-dependent manner into genuine fibrillar amyloid. Brain region selective αSYN neuropathology correlated with specific behavioral impairments, such as locomotor dysfunction and cognitive decline. Thus, the αSYN fibrillization process is tightly linked to neuropathology. The role and thus therapeutic potential of post-translational modifications (ubiquitinylation, oxidation, phosphorylation, truncation) and modifier genes on αSYN neuropathology can now be assessed in valid transgenic mouse models of α-synucleinopathies.     

Diagnostic staging of Parkinson’s disease: conceptual aspects

Summary. Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i.e. visual and olfactory dysfunction, with a resulting change of personal behaviour, i.e. reduced stress tolerance, precede the initially intermittendly occurring motor symptoms in patients with Parkinsons disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. We related these clinical observations of premotor symptoms of PD to this novel neuropathological concept of emerging neurodegeneration, which starts in the enteric system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons. We describe an initial premotor phase, which starts in non dopaminergic areas, and subdivide it according to the onset of gastrointestinal and brainstem associated and sensory deficits. Then motor symptoms occur and increase in the further course of PD similar to the Hoehn and Yahr stages. Our proposed diagnostic concept aims to an earlier diagnosis of PD. In addition, attention should be given to diseases of the gastrointestinal tract and psychosomatic disorders, all of which, if not or ineffectively treated, may contribute to an enhanced vulnerability for PD. The concept takes into account, that an as far unknown pathogen, e.g. viral infection or nutritional component, that meets a genetically predisposed person with a long lasting disturbed enteric nervous system, may be at risk for PD. Earlier premotor diagnosis of PD will enable more convincing future results on the therapeutic efficacy of neuroprotective compounds.     

Motor and non motor effects during intraoperative subthalamic stimulation for Parkinson’s disease

Spatial distribution of the clinical effects induced by deep brain stimulation during the intraoperative investigation of the subthalamic nucleus (STN) for Parkinsons disease (PD) was analysed in 17 patients under local anesthesia. The stimulation parameters were 130 hertz, 100 µs, and voltage ranged from 0.05 to 5 volts. Optimal motor response was assessed as the total and lasting disappearance of wrist rigidity on the side opposite to stimulation.Among the adverse effects induced by stimulation, special attention was given to frequently observed autonomic effects (AE). Full motor response was achieved in 49.2% of the 301 points evaluated,with a mean voltage (MV) of 0.94 volts; paresthesiae occurred in 6.6% (MV: 2 volts), dystonia in 10.6% (MV: 3.4 volts), autonomic effects in 19.6% (MV: 3.1 volts) and oculomotor effects in 31.6% (MV: 3 volts). The motor target was located in the posterodorsal part of the nucleus and the optimal point for motor response was close to the superior limit of the nucleus. Whereas other adverse effects occurred relatively far from the motor target, AE occurred with statistic significance near this point. Their neural substrates, such as limbic system and their relationship with postoperative behavioral disorders, are discussed.     

Deep brain stimulation in late stage Parkinson’s disease: a retrospective cost analysis in Germany

Abstract During the last few years, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as a promising therapy, alleviating major motor symptoms of Parkinsons disease (PD). However, in times of growing budgetary limitations, medical decisions are no longer merely based on clinical efficacy, but also on cost-effectiveness. Here we assess treatment costs (i. e. costs for conservative pharmacological treatment and all in-patient admissions) of 46 PD patients for one year before and two years after STN-DBS. The present data show that total treatment costs were increased by 32 % for the first year and decreased by 54 % for the second year of STN-DBS in comparison with preoperative values while the Unified Parkinons Disease Rating Scale (UPDRS III) was significantly improved. The increase for the first year after surgery was mainly due to the implantation of the STN electrodes and the stimulation device. Taken together, STNDBS pays off from the second year of stimulation while motor symptoms are significantly improved. The present study provides first data of an important number of patients on clinical effectiveness and expenses in relation to STNDBS.     

Analysis of polyglutamine-coding repeats in the TATA-binding protein in different neurodegenerative diseases

Summary. Trinucleotide repeat (TNR) expansion in the gene for TATA binding protein (TBP) has recently been described as causal for spinocerebellar ataxia type 17. The normal number of repeats has been considered to be 42 or less. An intermediate range with reduced penetrance has been assumed to be 43–47 CAA/CAG repeats. We examined this gene in 30 patients with autosomal-dominant cerebellar ataxia (ADCA), 35 patients with sporadic ataxia, 11 patients with Huntingtons disease (HD), 351 patients with idiopathic Parkinsons disease (PD), 105 patients with Alzheimers disease (AD), and 291 controls with no history of neurodegenerative disease. Three patients (one with sporadic PD and two with AD) carrying more than 42 TNRs in the TBP gene were identified. This reveals that the phenotype associated with CAG/CAA expansion in the TBP gene may be heterogeneous.These authors contributed equally to this work     

Only physical aspects of quality of life are significantly improved by bilateral subthalamic stimulation in Parkinson’s disease

Background The well known global improvement of quality of life (QoL) after bilateral high frequency chronic deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinsons disease (PD) is in contrast to behavioral disturbances as observed after surgery. Indeed the impact of DBS on physical versus mental aspects of QoL in PD remains unknown. Objective To assess the influence of bilateral STN DBS on physical versus mental aspects of QoL in Parkinsons disease. Methods The results of 27 patients for the Unified Parkinsons disease Rating Scale (UPDRS), Parkinsons Disease Questionnaire 39 (PDQ39) and Short Form 36 health survey questionnaire (SF36) were compared before surgery and after 12 months of bilateral STN DBS. Results Comparing off–dopa conditions before versus 12 months after surgery, both UPDRS part II and part III significantly improved: 32.6% and 52%, respectively. UPDRS part I scores did not change significantly at 12 months. As for PDQ39, the global score significantly improved after surgery (21.1 %) as did four subscores: mobility (25.6 %), activity of daily living (34.5 %), stigma (40.1 %) and bodily discomfort (30 %). Three PDQ39 subscores, however, showed no significant changes: emotional well–being (10.7 %), social support (3.2%) and cognition (8.5 %) and one item even worsened: communication (–7.7 %). In SF36, only physical items significantly improved. Conclusion Using clinicians based rating scale, bilateral STN DBS showed significant improvement in PD patients at 12 month follow up. However, using patients self–assessment scales, the clinical benefit of STN DBS was more subtle: physical items of QoL significantly improved, whereas mental items such as emotional well–being, social support, cognition and communication showed no improvement. Our results are suggestive of a dissociation of motor and non–motor symptoms control after bilateral STN DBS in PD patients.     

Pergolide effect on cognitive functions in early-mild Parkinson’s disease

Summary. In the present study, we evaluated the effect of pergolide, a mixed D1/D2 agonist, on cognitive function in mild Parkinsons disease (PD). After a two-week wash-out phase, twenty patients with a Hoehn and Yahr score 2.5 entered a 16-week, cross-over study in which the order of administration of pergolide or 1-dopa was randomly assigned. Cognitive assessment was performed after the wash-out phase and repeated after eight weeks (before patients were switched to the other drug) and at the end of the study. There were no significant differences in test scores among the three experimental modalities (off-treatment vs. l-dopa, off-treatment vs. pergolide, pergolide vs. l-dopa).In another cohort of comparably mild PD patients we had previously demonstrated that pramipexole, a mixed D2/D3 agonist, slightly but significantly worsened verbal fluency in comparison to l-dopa; moreover, pramipexole impaired short term verbal memory and attentional-executive functions in comparison to both l-dopa and the off-treatment condition. Taken together, these findings suggest that dopamine agonists may influence cognition in PD according to their pharmacological characteristics. Unlike the D2/D3 agonist pramipexole, pergolide and l-dopa, both of which stimulate D1- and D2-receptor subtypes, do not appear to impair cognitive function.     

Axonal transport defects: a common theme in neurodegenerative diseases

A core pathology central to most neurodegenerative diseases is the misfolding, fibrillization and aggregation of disease proteins to form the hallmark lesions of specific disorders. The mechanisms underlying these brain-specific neurodegenerative amyloidoses are the focus of intense investigation and defective axonal transport has been hypothesized to play a mechanistic role in several neurodegenerative disorders; however, this hypothesis has not been extensively examined. Discoveries of mutations in human genes encoding motor proteins responsible for axonal transport do provide direct evidence for the involvement of axonal transport in neurodegenerative diseases, and this evidence is supported by studies of animal models of neurodegeneration. In this review, we summarize recent findings related to axonal transport and neurodegeneration. Focusing on specific neurodegenerative diseases from a neuropathologic perspective, we highlight discoveries of human motor protein mutations in some of these diseases, as well as illustrate new insights from animal models of neurodegenerative disorders. We also review the current understanding of the biology of axonal transport including major recent findings related to slow axonal transport.     

Driving in Parkinson’s disease—a health hazard?

Abstract. Background: The driving safety of Parkinsons disease (PD) patients has lately been questioned after several authors reported road accidents caused by sleep attacks in PD patients on dopaminergic medication. Objectives: To determine 1) whether PD patients in general and those on dopaminergic medication in particular are especially prone to cause severe road accidents and 2) whether there are PD symptoms or dopaminergic side effects with the potential to compromise driving safety. Data source: Relevant articles were identified by electronic search of biomedical databases (1966–2002: MEDLINE, EMBASE, PASCAL, PUBMED), the Cochrane Controlled Trials Register, and reference lists of located articles. Results: Despite frequent occurrence of potentially hazardous dopaminergic side effects (2–57 %) and disabling parkinsonian non-motor and motor disabilities (16–63 %), the two existing studies on accident rates suggest that PD patients are not more prone to cause road accidents than the rest of the population. Five further reports including 1346 patients and focusing on dopaminergically induced sleep attacks provided comparably low accident figures (yearly incidence: 0%–2%). Because of low figures meta-analysis was intended but finally deemed inappropriate as the methodology of included studies varied greatly and was frequently flawed. Conclusion: Further prospective community-based well designed studies on accident risk in PD patients are needed to provide evidence based driving recommendations.     

Activation of basal ganglia loops in idiopathic Parkinson’s disease: a PET study

Summary. Patients with idiopathic Parkinsons syndrome (IPS) show dysexecutive deficits which are not related to dementia. We investigated whether these deficits may be caused by a disturbed interaction of prefrontal cortex and selective basal ganglia loops. 5 healthy right-handed volunteers and 5 non demented IPS patients were studied with FDG PET while performing a gambling task paradigm. Control subjects and patients showed consistent bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and the left caudate. Only controls activated the right cingulate, mesial prefrontal and frontoorbital cortex. Patients significantly deactivated the right thalamus. Thus missing frontoorbital and frontomesial activity may indicate an impairment of the basal ganglia loop in IPS, connecting those regions to the thalamus via the ventral striate. The connections between DLPFC and Thalamus via the left caudate remained intact. This impairment may be the neuroanatomical correlate for dysexecutive syndromes in IPS more related to misjudgement than cognitive impairment.Received May 8, 2003; accepted July 23, 2003     

Retrospective evaluation of cardio-pulmonary fibrotic side effects in symptomatic patients from a group of 234 Parkinson’s disease patients treated with cabergoline

Summary. Background: Cardiac valvulopathy has been recently associated with the use of the ergot dopamine agonist (EDA) pergolide in Parkinsons disease (PD). Cabergoline a widely used, well-tolerated EDA which has also been recently implicated in relation to fibrotic side effects although the evidence base for this is not sound.Aims: In PD patients on chronic cabergoline therapy, do symptoms suggestive of serosal/cardiac fibrosis imply underlying fibrotic lesions?Methods: A retrospective data review of 234 PD cases from three UK centres, on chronic cabergoline monotherapy or adjunctive treatment to identify symptoms suggestive of pleuro-pulmonary, cardiac or retroperitoneal fibrosis. These causes were thereafter selectively examined by appropriate specialists with relevant investigations.Conclusions: Out of 234 cases, 15 were identified with symptoms suggestive of respiratory, cardiac or abdominal systems involvement although subsequent investigations failed to reveal definite association with cabergoline except two cases with probable alveolitis and a possible association with cardiac murmur in one case. In spite of the deficiencies of a retrospective study, the results suggest a low risk of fibrotic side effects with cabergoline, particularly cardiac valvulopathy.     

Different mechanisms of corpus callosum atrophy in Alzheimer’s disease and vascular dementia

Abstract. Previous neuroimaging studies have indicated that corpus callosum atrophy in Alzheimers disease (AD) and large vessel occlusive disease (LVOD) is caused by interhemispheric disconnection, namely Wallerian degeneration of interhemispheric commissural nerve fibers originating from pyramidal neurons in the cerebral cortex. However, this hypothesis has not been tested from a neuropathological viewpoint. In the present study, 22 brains with AD (presenile onset, 9; senile onset, 13), 6 brains with Binswangers disease (BD), a form of vascular dementia and 3 brains with LVOD were compared with 6 non-neurological control brains.White matter lesions in the deep white matter and corpus callosum were quantified as a fiber density score by image analysis of myelin-stained sections. Axonal damage and astrogliosis were assessed by immunohistochemistry for amyloid precursor protein and glial fibrillary acidic protein, respectively.The corpus callosum thickness at the anterior part of the body was decreased in AD and LVOD,but not in BD significantly, as compared with the controls. The corpus callosum thickness correlated roughly with brain weight in AD (R = 0.50),and with the severity of deep white matter lesions in BD (R = 0.81). Atrophy of the brain and corpus callosum was more marked in presenile onset AD than in senile onset AD. With immunohistochemistry, the corpus callosum showed axonal damage and gliosis with a decreased fiber density score in BD and LVOD, but not in AD. Thus, corpus callosum atrophy was correlated with brain atrophy in AD, which is relevant to the mechanism of interhemispheric disconnection,whereas corpus callosum lesions in BD were secondary to deep white matter lesions. Corpus callosum atrophy in LVOD may indicate interhemispheric disconnection, but focal ischemic injuries may also be involved.     

Postnatal decrease in substantia nigra echogenicity

Abstract Increased echogenicity of the substantia nigra (SN) on transcranial ultrasonography (TCS) is a typical sign in Parkinsons disease (PD). Detected in healthy adults it is assumed to represent a risk factor for nigral injury. We studied at which time point of brain maturation increased signal intensity may occur by performing TCS scans in 109 newborns and children aged 0–192 months. While newborns regularly exhibit SN hyperechogenicity, this echofeature decreases substantially during the first years of life. As SN echogenicity is related to the tissue iron content in adults our findings suggest a failure in SN iron metabolism in some children with increased echogenicity during development which can be disclosed by TCS.