Hisayuki Kowa

A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1

We performed genomewide linkage analysis of a Japanese family with autosomal dominant parkinsonism, which exhibits clinical features compatible with those of common Parkinsons disease. Parametric two‐point linkage analysis yielded a highest log odds (LOD) score of 4.32 at D12S345 (12p11.21). Parametric multipoint linkage analysis of the 13.6cM interval around this marker yielded LOD scores almost uniformly of >4.0 with a Zmax of 4.71 at D12S85 (12q12). Haplotype analysis detected two obligate recombination events at D12S1631 and D12S339 and defined the disease‐associated haplotype in the 13.6cM interval in 12p11.2–q13.1. This haplotype was shared by all the patients and by some unaffected carriers, suggesting that disease penetration in this family is incomplete. This low penetrance suggests that environmental or other genetic factors modify expression of the disease. Nonparametric two‐point and multipoint linkage analyses, which are penetrance‐independent, yielded Zmax LOD scores of 14.2 and 24.9 at D12S345, respectively, strongly supporting the mapping of the parkinsonism locus in this family to 12p11.23–q13.11. This chromosome region is different from any known locus for hereditary parkinsonism, in keeping with the unique genetic features of the parkinsonism in this family. The nomenclature of PARK8 was assigned to the new locus.

An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family

We detected a missense mutation in the kinase domain of the LRRK2 gene in members with autosomal dominant Parkinsons disease of the Japanese family (the Sagamihara family) who served as the basis for the original defining of the PARK8 Parkinsons disease locus. The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure–pathogenesis relationship for the gene product of LRRK2. We did not detect this mutation or other known mutations of the LRRK2 gene in Japanese patients with sporadic Parkinsons disease. Ann Neurol 2005

Association of anti-GM2 antibodies in Guillain-Barré syndrome with acute cytomegalovirus infection

We examined serum anti-cytomegalovirus (CMV) and anti-ganglioside antibodies by ELISA in 51 patients with Guillain-Barré syndrome (GBS), and titers were compared with those from 47 normal and 74 disease controls. Three GBS patients with IgM anti-CMV antibodies had high titers of IgM and IgG anti-GM2 antibodies. The other GBS patients without IgM anti-CMV antibodies, and the normal and disease controls except one of 6 non-GBS patients with acute CMV infections had no anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These findings suggest that anti-GM2 antibodies are associated with acute CMV infections in GBS patients.

Randomized, double‐blind study of pramipexole with placebo and bromocriptine in advanced Parkinson's disease

We compared the efficacy and safety of pramipexole (PPX) with placebo in the treatment of advanced Parkinsons disease (PD) as an adjunct to levodopa. A bromocriptine (BR) group was included to enable determination of the noninferiority of PPX relative to BR as the standard treatment.

Autosomal Dominant Familial Parkinson Disease: Older Onset of Age, and Good Response to Levodopa Therapy

Autosomal dominant Parkinsons disease in 5 generations of a family living in Sagamihara City is reported. Clinical features of this family did not differ from common PD, however, neuropathological findings were different from PD. In autopsied cases, the loss of melanin-containing cells was mild to moderate, and the number of neurons of the locus ceruleus was maintained. No Lewy bodies were detected at all from any region where Lewy bodies frequently appear in PD.

Kinesin and cytoplasmic dynein in spinal spheroids with motor neuron disease

Kinesin and cytoplasmic dynein are two major molecular motors responsible for fast axonal transport. As visualized by immunohistochemistry with monoclonal antibodies, both motors were found to be distributed throughout the cell bodies, dendrites and axons of motor neurons in normal human spinal cords. Large axonal swellings, spheroids, in the spinal cords of patients with motor neuron disease showed massive accumulation of kinesin co-localized with highly phosphorylated neurofilaments. Of 114 spheroids in five spinal cords, 87% were stained heavily with the three anti-kinesin antibodies used in this study. Cytoplasmic dynein was scarce or absent in most of the spheroids. These findings suggest that kinesin selectively accumulates in the spheroids of motor neuron axons, causing disturbance of the machinery for anterograde fast axonal transport in motor neuron disease.

Extrapyramidal system involvement in motor neuron disease

Three cases of motor neuron disease (MND), in which neuropathological findings were atypical, are reported. The first case manifested widespread and severe degeneration of the spinal cord, as in spinal fibrosis. Case 2 revealed severe degeneration of the pyramidal tract with many spheroids, which made it difficult to differentiate from primary amyotrophic lateral sclerosis. The last case revealed degeneration of the nigro-pallido-luysian system, even though no clinical manifestation of extrapyramidal and/or cerebellar symptoms had been noted throughout the clinical course. In MND, degeneration might occur in various locations other than the motor system.

Nation-wide collaborative study on the long-term effects of bromocriptine in the treatment of parkinsonian patients. Final report.

Final results of the 5-year multicentric collaborative study on the long-term effects of bromocriptine in the patients with Parkinsons disease are reported. This prospective study started in May 1985 in order to see whether the early combination therapy with bromocriptine and levodopa is really superior to the levodopa monotherapy with regard to the late side effects of levodopa in the treatment of parkinsonian patients. Another project of the study was to see the therapeutic efficacy of bromocriptine monotherapy without concomitant use of levodopa. For these purposes, a total of 702 patients with Parkinsons disease were enrolled into three groups: Group 1 (n = 286) with bromocriptine monotherapy, Group 2A (n = 216) with early combination of bromocriptine and levodopa, and Group 2B (n = 200) with levodopa alone. At the end of the 5-year study, 48 patients in Group 1 (16.8%) were still continuing bromocriptine monotherapy with satisfactorily good therapeutic effects. About half (49.1%) of the Group 2A patients remained on the combined therapy, and the comparable number of the Group 2B patients (46.0%) were also kept on the initial mode of therapy, while 13.5% of the latter group with levodopa monotherapy needed bromocriptine to be added in order to assure the good therapeutic effects. Moreover, significant differences were seen between group 2A and Group 2B with regard to the incidence of wearing-off phenomenon and dyskinesias. Disappearance rate of dyskinesias which were present at the time of enrollment was significantly higher in Group 2A than in Group 2B. No significant difference was noted as to the incidence of untoward symptoms and the death rate among all three therapeutic groups. These results support the view that the early combination of bromocriptine with levodopa is superior to levodopa alone in the treatment of Parkinsons disease.

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

SummaryThe effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinsons 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 Parkinsons 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% 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 a useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

A Nationwide Collaborative Study on the Long-Term Effects of Bromocriptine in Patients with Parkinson’s Disease

The interim results of the nationwide collaborative study on the long-term effects of bromocriptine in patients with Parkinsons disease are reported. Four years ago, two prospective clinical studies were started to evaluate the long-term effects of bromocriptine in Parkinsons disease. The first was to investigate the long-term effects of bromocriptine monotherapy and the second to see the long-term effects of a combination therapy of bromocriptine with levodopa. Patients who had never been treated with levodopa were placed on bromocriptine monotherapy, and those who had been treated with levodopa for not more than 5 years were allocated randomly to either the combination or the levodopa group. Two hundred and eighty-six patients were enrolled in the former study and 416 in the latter. Among the 286 patients, 164 continued for further observation at the end of the fourth year, and 74 of them were still being treated with bromocriptine monotherapy. However, in 78, levodopa had to be added. Among the 416 patients in the second study, 216 were allocated to the combination group and 200 to the levodopa control group. At the end of the fourth year, 130 in the former and 140 in the latter group remained for further observation. In all three groups, a gradual loss of efficacy was noted. The rate of efficacy loss appeared largest in the monotherapy group and smallest in the combination group. Effects on tremor and rigidity are still maintained, but effects on akinesia and gait were lost by the end of the fourth year in all groups. Wearing-off and dyskinesias seem to be better managed by the combination therapy. The incidence of wearing-off was very small in the monotherapy group. No serious side effects were encountered except for 1 patient who died of pulmonary fibrosis in the combination group.