[Executive function in Parkinson's disease].

Executive function declines in Parkinson's disease (PD). However, it has not been clearly shown at what stage in PD, this decline starts to occur. We here report a study aiming to answer this question. We conducted Wisconsin Card Sorting Test (WCST) and Trail Making Test A and B (TMT A, B) in three normal control groups (young, adult, and aged) and three PD patients groups (Hoehn & Yahr stage I, II, and III). We intend to analyze at what age or stage the decline in executive function would take place. The score of all the normal subjects and PD patients were 25 points or above by Mini-Mental State Examination. WCST in stage I PD patients (mean age 60.8, n = 9) was essentially same as those of young normal (mean age 23.1, n = 9) and adult normal (mean age 61.5, n = 10) subjects. Elderly normal subjects (mean age 75.8, n = 4) showed a significantly lower mean category achievement score (3.0 as the mean score) and higher numbers of errors and perseverations compared with those of young and adult normal subjects. Stage II (mean age 62.6, n = 8) and III PD (mean age 62.9, n = 8) patients showed significantly lower mean category achievement scores (2.4 and 2.1, respectively as the mean scores) and higher numbers of errors and perseverations compared with those of adult control subjects (5.4 as a mean score). TMT (B-A) in elderly normal subjects revealed significantly longer score (209 seconds as the mean score) compared with those of young and adult normal subjects (20 and 45 seconds, respectively as the mean scores). TMT (B-A) in stage III PD patients was significantly longer (219 seconds) compared with that of adult normal subjects (45 seconds as the mean), however TMT (B-A) in stage II PD patients (102 seconds as the mean) did not show prolongation. TMT (B/A) showed essentially similar results as TMT (B-A), however, stage II PD patients showed significant prolongation compared with that of normal adult subjects. Therefore, TMT (B/A) appears to be a more sensitive indicator of decline in executive function in PD. Between WCST and TMT, the former appeared to be a more sensitive indicator. Our results indicate that the decline in executive function takes place in normal ageing. In PD, this decline starts much earlier than the normal subjects. The onset in this decline coincides with the stage of PD, in which bilateral symptoms start to present. Anatomo-chemical subsrate of cognitive decline in PD is still to be debated, however, we believe that involvement of nigro-caudatal projection is at least in part responsible, as nigroputaminal pathway is mainly involved in motor functions. We also point out the importance of age factor in the evaluation of cognitive-executive function in PD, as this function is age-dependent in normal subjects.

Neuropsychological outcome following pallidotomy and thalamotomy for Parkinson's disease.

Cognitive and emotional outcomes were assessed after unilateral posteroventral pallidotomy (PVP) and ventral intermediate nucleus thalamotomy (Vim-Th) in patients suffering from idiopathic Parkinson's disease (PD). PVP was performed on 12 PD patients (8 men and 4 women, mean age 56.4 years, 6 left lesions and 6 right lesions) and Vim-Th was performed on 13 PD patients (5 men and 8 women, mean age 63.2 years, 6 left lesions and 7 right lesions). In both the PVP group and the Vim-Th group, the Hoehn and Yahr staging scores (p < 0.01) and the Unified Parkinson's Disease Rating Scale activities of daily living and motor scores (p < 0.001) improved significantly. No significant changes in cognitive function were observed 4 weeks after unilateral PVP or Vim-Th. PVP produced a significant decline in Hasegawa's Dementia Scale-Revised scores in immediate postoperative assessments (p < 0.05), which resolved 4 weeks after surgery. While the Minnesota Multiphasic Personality Inventory depression and social introversion scores improved significantly in the Vim-Th group (p < 0.01 and p < 0.05, respectively), the hypochondriasis and hypomania scores improved significantly in the PVP group (p < 0.01 and p < 0.05, respectively). We conclude that PVP and Vim-Th influence postoperative emotional status rather than postoperative cognitive status.

[Clinical pathophysiology of parkinsonian symptoms: from experiences of stereotaxic surgery].

Pathophysiological mechanisms of major symptoms of Parkinson's disease are discussed from experiences of stereotaxic surgery. Tremor completely disappears by a lesion in the ventral intermediate nucleus(Vim) which receives proprioceptive sense from the periphery. Rigidity is alleviated by a lesion in the globus pallidus(GP) and the ventral lateral nucleus(VL) equally. Since GP projects to the prefrontal motor cortex via VL, surgery to either of those structures causes the same result. Akinesia is classified into three types: secondary akinesia, primary akinesia, and akinesia due to psychomotor dysfunction. Gradual spread of neuronal degeneration within the substantia nigra pars compacta may explain the progression of akinesia. Psychological or psychiatric disorder becomes major symptom in the late stage. Posteroventral pallidotomy may change emotional state in some cases by influencing the limbic motor circuit.

[Usefulness of exercise echocardiography in ischemic heart disease: comparison with exercise cardiac scintigraphy].

Exercise echocardiography and exercise thallium-201 (201Tl) single photon emission computed tomography (SPECT) were performed in 152 patients with suspected coronary artery disease, including 61 patients with old myocardial infarction. All patients underwent coronary arteriography, and coronary artery disease was defined as > or = 75% diameter stenosis. Digital two-dimensional echocardiography was performed before and after the treadmill exercise test, and wall motion abnormality was evaluated using quad-screen. Sensitivity and specificity for the diagnosis of coronary artery disease were similar for the 2 exercise tests (77% and 80% for echocardiography and 75%, and 83% for SPECT, respectively). Diagnoses for one-vessel disease, 2-vessel disease and 3-vessel disease were similar for echocardiography (79%, 72% and 77%, respectively) and SPECT (74%, 75% and 77%, respectively). Sensitivity for the diagnosis of ischemia at the area remote from infarct area was low for both exercise echocardiography and exercise SPECT (45% and 48%, respectively). Exercise echocardiography has comparable diagnostic value to SPECT for the detection of coronary artery disease. However, both exercise tests have limitations for the diagnosis of ischemia at the area remote from infarct area.

Safety study of lazabemide (Ro19-6327), a new MAO-B inhibitor, on cardiac arrhythmias and blood pressure of patients with Parkinson's disease.

To evaluate whether lazabemide has proarrhythmic or hypotensive potency in Parkinson's disease (PD), we conducted an 8-week, double-blind, placcbo-controlled, parallel group study with use of 24-hour ambulatory electrocardiographic (ECG) monitoring. Fifty-one patients with PD who did not have clinically apparent heart disease were randomized in a double-blind fashion to receive either lazabemide (n = 25) or placebo (n = 26) treatments. Lazabemide therapy did not induce clinically significant arrhythmias. A paroxysmal atrioventricular (AV) block, which progressed from first-degree AV block, was found in one patient in the lazabemide group. This was determined not to be a new AV block. However, the causality of lazabemide in prolongation of the pause was not ruled out completely. In addition, the asymptomatic fall in systolic blood pressure seen 3 minutes after standing up was observed to be more pronounced in the lazabemide group than in the placebo group. The mean decrease of systolic blood pressure was 10 mmHg greater in the lazabemide group than in the placebo group. In conclusion, lazabemide did not induce any clinically significant arrhythmias in patients without clinically apparent heart disease. However, it may increase the asymptomatic, orthostatic drop in systolic blood pressure.

Stereotactic surgery and Parkinson's disease.

With a short description of the historical background, thalamotomy and posteroventral pallidotomy (PVP) are introduced as effective means to alleviate motor symptoms in Parkinson's disease (PD). Rigidity and dopa-induced dyskinesia are improved and abolished by either of the two procedures, but tremor is more markedly improved by thalamotomy than by PVP. To date, surgical treatment has been important in treating PD. Also, the influence of PVP on psychological symptoms in PD, bradyphrenia and emotional changes offers an important key to understand and to interpret these symptoms.

Neuronal activity in GP and Vim of parkinsonian patients and clinical changes of tremor through surgical interventions.

Microrecordings were performed during pallidotomy and thalamotomy for Parkinson's disease (PD). Neuronal activity in globus pallidus (GP) was in general agreement with previous studies of human and primate models of PD. Neuronal activity, where frequency of tremor appeared to oscillate independently from peripheral input, was encountered in GPi. In contrast, neuronal activity in Vim regarding frequency of firing also correlated with tremor and was passively driven by kinesthetic stimuli with a somatotopic arrangement. Pallidal lesions based on microrecording induced relative reductions of tremor, while small Vim lesions immediately alleviated tremor. Basal ganglia pathology due to dopamine depletion could generate oscillatory neuronal activity in GPi, which may cause tremor. However, peripheral feedback to the motor cortex via Vim is also significant for tremorgenesis, because Vim may be an excitatory driving source for motor cortical neurons. Thus, a Vim lesion could reduce excitability of the motor cortical neurons and abolish tremor.

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson's disease.

The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

Posteroventral pallidotomy: its effect on motor symptoms and scores of MMPI test in patients with Parkinson's disease.

Stereotaxic pallidotomy for Parkinson's disease (PD) is an old concept, which was gradually and mostly replaced by thalamotomy. Recently, posteroventral pallidotomy (PVP), originally proposed by Leksell et al., was reintroduced; this paper examines PVP in terms of its historical background, technical aspect and location of the surgical lesion, as well as clinical effects on motor and psychological symptoms. Posteroventral pallidotomy has been shown to be satisfactory in relieving rigidity and secondary akinesia, but not powerful enough in alleviating severe tremor. These are similar observations to those made in classical pallidotomy. For this reason, all PVP-treated cases reported in this paper have an additional small thalamic lesion for control of tremor. Also, it must be recognized that most of the surgically treated patients are continuing to take medication at the same or slightly lowered dose compared with preoperatively. Dopa-induced dyskinesia is alleviated well by PVP, similar to thalamotomy. The most important question is whether PVP has more effect on truncal symptoms, such as postural imbalance, and on gait than thalamotomy, a question that is still not satisfactorily answered in both clinical and basic analysis. Parkinson's disease-induced changes in emotional status, such as depression or hypochondriacal complaints, are favorably influenced by PVP, but not by thalamotomy. The role of stereotaxic surgery in the era of pharmacological treatment is discussed, as is the possible importance of the role of the limbic-motor circuit in research on PD.

Pallidotomy revisited. Analysis of posteroventral pallidotomy.

Posteroventral pallidotomy (PVP) has been shown to alleviate motor symptoms in Parkinson's disease (PD), e.g., rigidity, secondary akinesia due to existence of muscle rigidity and slight tremor, but not the marked tremor. For the latter, additional lesion of the ventral intermediate nucleus of the thalamus is necessary. Akinesia was divided into three subtypes, and the influence of PVP on each type is described. Primary akinesia is not changed by either PVP or thalamotomy but responds well to L-dopa. Psychological symptoms, i.e., depressive mood, loss of initiation or abulia, and lowered emotional activity, which are generally termed as bradyphrenia, benefit well from PVP but less from thalamotomy. This effect is interpreted as due to the lesion extending into the ventral pallidum, where a small posterior part of the limbic-motor projections may possibly be involved. Such experience suggests that the third type of akinesia in PD, named the 'psychomotor or limbic-motor type' by the author, can be improved by the surgical procedure on the ventral globus pallidus. These observations offer an important chance to understand the psychological symptoms in PD as a result of dopamine deficiency of ventral tegmental area neurons projecting to the ventral striatum, which further influences the ventral pallidum.

The soluble form of Fas molecule is elevated in parkinsonian brain tissues.

Fas is an apoptosis-signaling receptor molecule on the surface of a number of cell types. The soluble form of Fas (sFas) was measured for the first time in brain (caudate nucleus, putamen and cerebral cortex), ventricular cerebrospinal fluid (VCSF), and lumbar CSF (LCSF) from control and parkinsonian patients by a highly sensitive two-site sandwich enzyme-linked immunosorbent assay (ELISA). The concentrations of sFas in nigro-striatal dopaminergic regions were significantly higher in parkinsonian patients than those in controls, whereas this product in cerebral cortex showed no significant difference between parkinsonian and control subjects. Neither VCSF nor LCSF contained the sFas molecule in the detectable amounts (< 16 pg/ml). These results suggest that the presence of sFas possibly leads to cell death/neurodegeneration in parkinsonian brain.

bcl-2 protein is increased in the brain from parkinsonian patients.

The proto-oncogene bcl-2 is involved in the regulation of cell death and may be able to block apoptosis in neurons through reduced generation of reactive oxygen species (ROS). The bcl-2 product was measured for the first time in brain (caudate nucleus, putamen and cerebral cortex), ventricular cerebrospinal fluid (VCSF), and lumber CSF (LCSF) from control and parkinsonian patients by highly sensitive two-site sandwich enzyme-linked immunosorbent assay (ELISA). The concentrations of bcl-2 in the nigrostriatal dopaminergic regions were significantly higher in parkinsonian patients than those in controls, whereas this product in cerebral cortex showed no significant difference between parkinsonian and control subjects. Neither VCSF nor LCSF from control or parkinsonian subjects contained the bcl-2 product in the detectable amount (< 5 U/ml). Since oxidative stress may be involved in neurogenerative disorders, accumulation of bcl-2 may reflect a mechanism for counterbalancing ROS-mediated damage, or it might represent the impairment of bcl-2-dependent protection from ROS in parkinsonian brain.

The metabolism of L-DOPA and L-threo-3,4-dihydroxyphenylserine and their effects on monoamines in the human brain: analysis of the intraventricular fluid from parkinsonian patients.

The monoamines and their metabolites were analyzed in the intraventricular fluid of parkinsonian patients treated with L-DOPA alone or together with L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), the precursor amino acids of dopamine and noradrenaline, respectively. In the intraventricular fluid of the patients administered with L-DOPA, the level of dopamine metabolites were higher than control, suggesting enhanced turnover of dopamine in the brain. However, L-DOPA administration increased free noradrenaline only slightly, and did not affect serotonin and its metabolite. On the other hand, by administration of L-DOPA combined with L-threo-DOPS, the levels of monoamines increased in general, whereas the monoamine metabolites by catechol-O-methyltransferase were reduced compared with those in the patients treated with L-DOPA alone. Only a minor part of L-threo-DOPS was metabolized into noradrenaline by aromatic L-amino acid decarboxylase, and it was metabolized mainly by two other enzymes, catechol-O-methyltransferase and DOPS-aldolase in the brain. An overview of the metabolism of neurotransmitters in the brain proved to be useful to evaluate the therapeutic effects of these precursor amino acids.

Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease.

Interleukin (IL)-1 beta , IL-2, IL-4, IL-6, epidermal growth factor (EGF), and transforming growth factor (TGF)-alpha were measured for the first time in ventricular cerebrospinal fluid (VCSF) from control non-parkinsonian patients, patients with juvenile parkinsonism (JP) and patients with Parkinson's disease (PD) by highly sensitive sandwich enzyme immunoassays. All cytokines were detectable in VCSF from control and parkinsonian patients, and the concentrations were much higher than those in lumbar CFS. The concentrations of IL-1 beta, IL-2, IL-4 and TGF-alpha in VCSF were higher in JP than those in controls (P < 0.05). In contrast, the concentrations of IL-2 and IL-6 in VCSF from patients with PD were higher than those from control patients (P < 0.05). These results agree with our previous reports, in which the cytokine levels were elevated in the striatal dopaminergic region of the brain from patients with PD. Since VCSF is produced in the ventricles, the alteration of cytokines in VCSF may reflect the changes of cytokines in the brain. Because cytokines play an important role as mitogens and neurotrophic factors in the brain, the increases in cytokines as a compensatory response may occur in the brain of patients of JP or PD during the progress of neurodegeneration. Increase in cytokines may contribute not only as a compensatory response but as a primary initiating trigger for the neurodegeneration.

GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia.

Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon I of the GTP-CH I gene and a new mutation at the splice acceptor site of intron I were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.

Stereospecific occurrence of a parkinsonism-inducing catechol isoquinoline, N-methyl(R)salsolinol, in the human intraventricular fluid.

N-Methyl(R)salsolinol, an endogenous neurotoxin, has been proposed to be closely involved in the pathogenesis of Parkinson's disease. The selective toxicity to dopaminergic neurons was strictly limited for (R)-enantiomer of N-methylsalsolinol. Its precursor, (R)salsolinol was enzymatically synthesized from dopamine and acetaldehyde in human. However, it has never been examined whether a non-enzymatic reaction produces racemic salsolinol derivatives from dopamine especially in patients under L-DOPA therapy. To clarify the point, their contents were examined in intraventricular fluid from parkinsonian patients administrated with L-DOPA. Only (R)-enantiomer of N-methylsalsolinol and very low concentration of salsolinol could be detected. The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism. The results are discussed in relation to pathogenesis Parkinson's disease.