Association of the human leucocyte antigen region with susceptibility to Parkinson's disease.

OBJECTIVE: The core pathology of Parkinson's disease (PD) is a loss of the dopaminergic neurons in the nigro-striatal pathway, but this is only part of a more widespread pathological process, the nature of which is unknown. Recent data suggest a possible role for inflammation in this disease process. The Human Leucocyte Antigen (HLA) region is one of the most important genetic susceptibility factors in many immune-mediated diseases but has not been extensively investigated in PD. METHODS: The authors typed the HLA class II loci HLA-DRB1 and -DQB1 in 528 patients with Parkinson's disease and 3430 controls from the UK. RESULTS: The authors observed an association of HLA-DRB1 with susceptibility to Parkinson's disease. In particular, HLA-DRB1*03 was more common in patients compared with controls. CONCLUSIONS: These data suggest a possible role of the HLA region in susceptibility to Parkinson's disease and as such are consistent with other evidence supporting the role of an inflammatory process in the cellular loss in Parkinson's disease, especially of the nigral dopaminergic neurons.

Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson's disease.

Further to the well-established association between apolipoprotein E (APOE) and Alzheimer's disease, this gene has also been implicated in both susceptibility to, and dementia in, Parkinson's disease (PD). However studies to date have produced contradictory findings. We conducted a case-control study in a population of 528 PD patients and 512 healthy controls and found no significant difference in allele or genotype distribution of APOE between the two groups. An updated meta-analysis showed a modest increase of APOE-epsilon2 carriers amongst PD patients compared to controls [P = 0.017, OR = 1.16 (95 % CI 1.03-1.31)]. 107 of our patients were incident cases participating in a population-based epidemiological study. Longitudinal follow-up of this cohort over a mean of 5.0 +/- 0.7 years from diagnosis revealed no significant impact of APOE-epsilon4 carrier status on risk of dementia or rate of cognitive decline. An updated meta-analysis indicated an over-representation of APOE-epsilon4 carriers amongst PD dementia compared to non dementia cases [OR 1.74 (1.36-2.23), P = 1 x 10(-4)], although small sample sizes, heterogeneity of odds ratios and publication bias may have confounded this finding. In conclusion, our study does not support previously reported associations between APOE genotype and susceptibility to, or cognitive decline in, PD. An updated meta-analysis indicates any association with PD susceptibility is at most modest, an observation with important implications for further study of this issue. Large scale longitudinal studies would be best placed to further evaluate any impact of APOE genotype on cognitive decline in PD.

Primary skeletal muscle involvement in chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a hereditary disease characterized by involuntary movements and amyotrophy with elevation of serum creatine kinase. Although skeletal muscle involvement in ChAc has been suggested, the mechanism remains unclear. To investigate chorein abnormalities of the skeletal muscles of ChAc patients with an apparently heterozygous VPS13A mutation compared with those of other hereditary choreic diseases, we performed histological and immunohistochemical studies of the skeletal muscles from 3 ChAc, 1 Huntington's disease (HD), 1 McLeod syndrome (MLS), and 1 normal control (NC) with 2 originally generated anti-chorein antibodies. Chorein immunoreactivities in HD, MLS, and NC were found linearly along the sarcolemma and appeared as speckles in the sarcoplasma, but those in ChAc were uneven and discontinuous along the sarcolemmas and increased in the sarcoplasma especially in type I fibers. This histological observation suggests chorein abnormalities of skeletal muscles might be associated with primary involvement of skeletal muscles in this disorder.

Neurological deficits are associated with increased brain calcinosis, hypoperfusion, and hypometabolism in idiopathic basal ganglia calcification.

We report two familial cases of idiopathic basal ganglia calcification. A 60-year-old proband with choreoathetosis, dysarthria, and cognitive decline showed more extensive brain calcinosis, hypoperfusion, and hypometabolism than did his asymptomatic 82-year-old mother. The mother had no frontal lobe calcinosis but basal ganglia and dentate nucleus depositions were detectable. Perfusion neuroimaging, however, was normal in the asymptomatic mother and abnormal in the clinically impaired proband. The presence of calcinosis cannot be used as an index of neurological impairment but the extent of calcinosis and reduction in perfusion and metabolism may be useful for separating symptomatic from asymptomatic subjects with IBGC. These findings suggest that an interruption of neuronal circuitry may cause neurological deficits. The degree of neurological deficits may correlate with the severity of calcinosis and the reduction of perfusion and metabolism.

[Ictal alteration of 99mTc ECD SPECT imaging in a patient with secondary paroxysmal kinesigenic dyskinesia caused by hyperglycemia].

We described a 61-year-old man with diabetes mellitus who presented with hyperglycemia related paroxysmal kinesigenic dyskinesia (PKD) with sudden development of paroxysmal unilateral involuntary movements (IMs) of his neck and the left extremities. Ictal 99mTc-ethylcysteinate dimer SPECT (ECD-SPECT) revealed a hyperperfusion over the contralateral frontal cortex and a hypoperfusion over the contralateral basal ganglia. Immediate correction of hyperglycemia after admission resulted in a marked improvement of IMs and a return to normal cerebral blood flow on interictal ECD-SPECT imaging. These findings suggest that dysfunction of the indirect pathway through the basal ganglia lead to an imbalance of the cortico-striato-thalamo-cortical circuit and may have contributed to the cause of PKD in this case.

Induction of humoral responses specific for paraneoplastic cerebellar degeneration-associated antigen by whole recombinant yeast immunization.

Paraneoplastic cerebellar degeneration (PCD) is a potent autoimmune disorder in which antigen-driven responses toward the onconeural antigen are assumed to occur in patients. Yeast cell wall has adjuvant capacity and provides immunostimulatory effects of the antigen expressing in viable cells. The recombinant yeast expressing the PCD-associated antigen may become an immunogen for inducing PCD-associated autoimmunity in mice. We attempted to induce autoimmune responses with whole recombinant yeast expressing PCD-associated antigen. SJL/J strain of mouse is found to be a responder to the major epitope on the antigen for anti-Purkinje cell antibodies, and whole recombinant yeast could induce cellular and humoral autoimmune responses in vivo ion SJL/J mice. The immunization technique based on the recombinant yeast expressing a PCD-associated antigen provides a new tool for analyzing the underlying immunological pathomechanisms of PCD.

Chorea-acanthocytosis associated with Tourettism.

We report on a case of Chorea-acanthocytosis (ChAc) in association with Tourettism that consisted of motor and vocal tics, attention deficit-hyperactivity disorder, and obsessive-compulsive disorder in addition to the typical symptoms of ChAc. The subject was compared with his elder sister who had the same disease but milder clinical profile and neuroradiological findings. The [(18)F]-2-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) findings did not explain the differences in symptomatology between the patient and his sister, although they may have correlated with severity.

Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD.

OBJECTIVE: Cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy studies of patients with idiopathic Parkinson's disease (PD) found decreased uptake. Whether this decrease is associated with clinical severity as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the phenotypes of PD has not been determined. METHODS: Cardiac MIBG scintigraphy was performed on 34 patients with PD, 7 with multiple system atrophy (MSA), 4 with dementia with Lewy bodies (DLB), and 11 normal controls (NCs). Early and delayed MIBG heart/mediastinum (H/M) ratios were evaluated. PD severity was assessed by the Hoehn and Yahr (H-Y) stage and UPDRS. Patients were grouped in two phenotypes, tremor and postural instability gait difficulty (PIGD)-dominant groups based on UPDRS components. Associations between MIBG uptake and age at onset, UPDRS, and disease phenotype were analyzed in each group. RESULTS: The early H/M ratio was significantly lower in patients with PD (1.45+/-0.207) than in the NCs (2.08+/-0.231), and in those with MSA (1.99+/-0.284), but not in those with DLB (1.29+/-0.0435). The delayed H/M ratio for PD (1.33+/-0.276) also was significantly decreased as compared to the ratios for NCs (2.17+/-0.286) and MSA (2.16+/-0.414) but not DLB (1.16+/-0.0949). The early H/M ratio was significantly correlated with both UPDRS score and age at onset, whereas the delayed H/M ratio only was significantly correlated with age at onset. The PIGD-dominant group had significantly higher UPDRS scores and lower H/M ratios than the tremor-dominant group. CONCLUSION: Cardiac MIBG scintigraphy can be used to differentiate PD from MSA and NC, and to determine the disease severity and phenotypes of PD.

Effect of a paraneoplastic cerebellar degeneration-associated neural protein on B-myb promoter activity.

In this study, we have shown that a paraneoplastic cerebellar degeneration (PCD)-associated antigen, pcd17, binds to a cell cycle-related protein, MRG15. MRG15 derepresses the E2F-responsive B-myb promoter. The pcd17 antigen inhibits the derepression of the B-myb transcriptional activity by MRG15, and, as a result, pcd17 represses the promoter. Delivery of anti-Purkinje cell antibodies (anti-Yo) into the cells inhibits the repression of B-myb promoter activity by pcd17. Because derepression of the B-myb promoter has been implicated in neuronal death, the results suggest the possible role of the antibodies in the pathogenesis of PCD.

Binding of the ELAV-like protein in murine autoimmune T-cells to the nonameric AU-rich element in the 3' untranslated region of CD154 mRNA.

The CD154 molecule is important for experimental allergic encephalomyelitis (EAE) which is mediated by autoimmune CD4(+) T-cells. Post-transcriptional instabilization/stabilization of mRNAs, which contain an adenylate uridylate rich element (ARE) in their 3' untranslated region (3'UTR), is regulated in part by binding of ARE-binding proteins to the element. We have investigated the protein which binds to the nonameric ARE in the 3'UTR of CD154 mRNA. A protein which binds to the CD154 ARE was found to exist in a extract prepared from murine autoimmune T-cells activated with myelin basic protein (MBP), and turned out to be mHuR which is a ubiquitous ELAV-like protein. It was found that mHuR was upregulated upon stimulation of the T-cells with a MBP antigen. The CD154 ARE and the ARE in the 3'UTR of tumor necrosis factor-alpha (TNF-alpha) mRNA were competed in binding to mHuR, indicating that both AREs bind to the same site on mHuR. The presence of the CD154 ARE downstream of the luciferase cDNA in a reporter plasmid decreased the translational efficiency, and co-expression of the mHuR slightly increased the translation. These results suggest the possibility that the ELAV-like protein participates in the regulation of the expression of CD154 on the autoimmune T-cells. Modification of the expression of CD154 on autoimmune T-cells by regulating the ELAV-like protein may provide effective therapy for EAE and human multiple sclerosis.

[A case of portal-systemic shunt encephalopathy due to congenital portal vein hypoplasia presenting with abnormal cerebral white matter lesions on the MRI].

A 49-year-old woman, without any past history of liver diseases and blood transfusion, was admitted to our service because of somnolence, and flapping tremor. Neurologically, she was drowsy and disoriented. She had bilateral pyramidal tract signs and flapping tremor. Although the laboratory examination showed marked hyperammonemia (217 micrograms/dl), neither abdominal CT nor liver biopsy showed any evidence of liver cirrhosis. An abdominal angiography showed portal vein hypoplasia associated with the portal-systemic shunt. A T2-weighted MRI showed the high intensity areas in the bilateral deep cerebral white matter, and the posterior limbs of the bilateral internal capsules. This is a rare case of portal-systemic shunt encephalopathy due to congenital portal vein hypoplasia presenting with abnormal cerebral white matter lesions on the MRI.

[A case of Gitelman's syndrome presenting with the hypokalemic periodic paralysis].

We report a rare case of Gitelman's syndrome (GS) presenting with the hypokalemic periodic paralysis. A 27-year-old man was admitted to our hospital because of transient weakness of the limbs. Past history was unremarkable, including the delivery and early developmental milestones, except for a transient limb weakness 7 times since the age of 15 years. The blood pressure was 140/90 mmHg. The physical examinations were unremarkable. Neurologically, the patient was fully oriented. The cranial-nerve functions were intact. Manual muscle tests revealed 1/5 weakness in his neck and extremities. Sensation was normal in all modalities. The deep tendon reflexes were present but decreased mildly. Laboratory tests showed hypokalemia (1.9 mEq/l), hypomagnesemia (1.8 mEq/l), and hypocalciuria (40.0 mg/dl). Plasma rennin activity and aldosterone concentration were elevated. The molar ratio of urinary calcium/creatinine was 0.11 (< 0.2). Arterial blood gas showed mild metabolic alkalosis with respiratory compensation. Because of these data, the diagnosis of GS was made. Gene mutations in the renal thiazide sensitive Na-Cl cotransporter (TSC) have already been shown to cause GS. Although we searched for gene mutation of TSC, none of 25 mutations in 18 out of 26 exons which had been previously reported were found. This is the first report of Gitelman's syndrome presenting with the hypokalemic periodic paralysis in Japan.