Teiko Kimpara

Microsatellite polymorphism in the human heme oxygenase-1 gene promoter and its application in association studies with Alzheimer and Parkinson disease

Abstract Oxidative stress has been suggested to be involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease (AD) and Parkinson disease (PD). Heme oxygenase-1 (HO-1), a key enzyme in heme catabolism, also functions as an antioxidant enzyme. Here, we show that a (GT)n repeat in the human HO-1 gene promoter region is highly polymorphic, although no particular alleles are associated with AD or PD. This newly identified genetic marker should allow us to study the possible involvement of HO-1 in certain human diseases.

Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease.

The changes of regional cerebral blood flow (rCBF) in Parkinsons disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn-Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinsons disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to L-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.

Increased bilirubins and their derivatives in cerebrospinal fluid in Alzheimer’s disease

Bilirubin, an efficient antioxidant, is the end product of the heme cleavage pathway, which is catalyzed by heme oxygenase (HO) and biliverdin reductase. Although an inducible form of HO is overexpressed in the Alzheimers disease (AD) brain, it has not been determined whether bilirubin metabolism is actually activated or not. In this study, we measured CSF-bilirubins and their derivatives using an enzyme-linked immunosorbent assay with two kinds of anti-bilirubin monoclonal antibodies, designated 24G7 and 5M2. In AD patients, the levels of CSF bilirubin derivatives increased significantly compared with those of controls. This increase was not due to the increased permeability of the blood-brain barrier, because the levels of unconjugated bilirubin were not different between AD and controls. These data may reflect the increase of degraded bilirubin metabolites in the AD brain derived from the scavenging reaction against chronic oxidative stress.

Regional difference in induction of heme oxygenase-1 protein following rat transient forebrain ischemia

Heme oxygenase (HO) is a rate-limiting enzyme in heme catabolism, the end products of which include iron, carbon monoxide and bilirubin. We investigated the changes in expression of an inducible form, heme oxygenase-1 (HO-1), and a constitutive form, HO-2, in rat brain following 20 min of forebrain ischemia, using specific antisera for HO-1 and HO-2. HO-1 protein was remarkably induced in brain following ischemia, while the level of HO-2 protein was not noticeably affected. The level of HO-1 protein expression was maximal at 12 h, which is in good agreement with the time course of the HO-1 mRNA induction. In the cortical mantle, most of the cells expressing increased HO-1 protein were identified as pyramidal neurons and astrocytes by their shapes and locations. In hippocampal CA-2 and CA-3 subfields, prominent induction was observed in astrocytes rather than in neuronal cells. By contrast, the HO-1 protein was not detected in the CA1 subfield following the insult, although the increased level of transcripts was evident in neurons and glial cells. These results suggest that not only in neuronal cells but also in astrocytes within the CA1 subfield, there may be an impairment of protein metabolism, preceding the delayed CA1 pyramidal cell losses.

BRIEF COMMUNICATION Mutation in the α-Synuclein Gene and Sporadic Parkinson's Disease, Alzheimer's Disease, and Dementia with Lewy Bodies

Abstract Recently, α-synuclein attracted attention when Polymeropoulos and colleagues identified a missense mutation of this gene ( Science 276:2045–2047, 1997), which is responsible for a form of early-onset familial Parkinsons disease (PD). Immunohistochemically, α-synuclein is localized in Lewy bodies, characteristic brain pathology of PD, dementia with Lewy bodies (DLB), and Alzheimers disease (AD), suggesting that this protein may link these common neurological diseases. Exploration of the possibility that the same mutation of the α-synuclein gene as that in familial PD (Ala53Thr) may also confer susceptibility to sporadic PD, DLB, and AD revealed the mutation in none of the samples of 329 cases and 230 controls examined, suggesting that this mutation is not involved in these neurological diseases.

Induction of Midkine Expression in Reactive Astrocytes Following Rat Transient Forebrain Ischemia

Midkine (MK), a retinoic acid-responsive gene product, is a 13-kDa heparin-binding protein with neurotropic activity. Previous studies demonstrated the expression of MK in embryonal and neonatal brains and its potent neurotropic activities in vitro. Data concerning its role in the mature central nervous system, however, are still limited. We examined the changes of MK expression in the adult rat brain following transient forebrain ischemia, by Northern blot, in situ hybridization and immunohistochemical analyses. In the control brain, MK mRNA was expressed in the cortical and hippocampal neurons. Following the ischemia, up-regulation of MK mRNA and a corresponding increase of its protein products were found in the hippocampal CA1 subfield. The maximal expression was demonstrated on day 4 after the insult. The cells expressing MK were distributed around the depleted CA1 pyramidal cells and identified as reactive astrocytes by double immunostaining. These data suggest that MK may be an insult-induced molecule which participates in the reparative processes following neuronal injury.

Characteristics of the increase in plasma brain natriuretic peptide level in left ventricular systolic dysfunction, associated with muscular dystrophy in comparison with idiopathic dilated cardiomyopathy

To determine whether the plasma brain natriuretic peptide level increases differentially in muscular dystrophy and idiopathic dilated cardiomyopathy, we investigated the plasma brain natriuretic peptide level and echocardiographic parameters in patients with similarly low left ventricular ejection fraction. The plasma brain natriuretic peptide level was lower, and the left ventricular end-diastolic diameter was shorter in the patients with muscular dystrophy than in those with idiopathic dilated cardiomyopathy. The correlation between the plasma brain natriuretic peptide and left ventricular ejection fraction was shifted downward in the patients with muscular dystrophy compared with those with idiopathic dilated cardiomyopathy. Those between the brain natriuretic peptide and left ventricular end-diastolic diameter were superimposable, although the data from the muscular dystrophy patients were located at the shorter left ventricular end-diastolic diameter side. The plasma brain natriuretic peptide level may differentially increase in the two diseases with similar left ventricular systolic dysfunction. Differences in the left ventricular distension and in the physical activity might explain at least partially the different plasma brain natriuretic peptide levels.

Assessment of cancer susceptibility in humans by use of genetic polymorphisms in carcinogen metabolism.

Prevention is an important and effective measure for reducing death caused by cancer. Thus information on individual susceptibility to cancer is valuable in suggesting high risk individuals to avoid intake of carcinogenic substances and receive frequent physical screening. To this end, polymorphisms found within cytochrome P450 (CYP) genes implicated in the metabolism of procarcinogens are expected to be good genetic targets in assessing human cancer susceptibility. We have found polymorphisms in the CYP2E1 and CYP1A1 genes associated with lung cancer susceptibility, though there were some discrepancies from observations made by other investigators. Discrepancies among investigators from different regions, however, are very common in these pharmacogenetic studies. We present an explanation for these discrepancies, difficulties associated with prediction of relative risk of individuals, and future directions.

Arg(184)his mutant GTP cyclohydrolase I, causing recessive hyperphenylalaninemia, is responsible for dopa-responsive dystonia with parkinsonism: A case report†

We describe a 54‐year‐old man with dominant adult‐onset dopa‐responsive dystonia (DRD) with parkinsonism caused by an Arg184His mutation in guanosine 5′‐triphosphate cyclohydrolase I (GCH‐I). This is the first mutation in the GCH‐I gene that has been proven to be responsible for both recessive and dominant phenotypes.

Neural substrates for writing impairments in Japanese patients with mild Alzheimer's disease: A SPECT study

Language is fairly well preserved in most patients with mild Alzheimers disease, but writing ability seems to be impaired even in the early stages of the disease. To investigate the neural bases of writing impairments in Alzheimers disease (AD), we examined the correlation between writing ability and regional cerebral blood flow (rCBF) in 52 Japanese patients with mild AD compared to 22 controls, using single photon emission computed tomography (SPECT). We found that, compared with control subjects, Kana writing to dictation and copying Kanji words were preserved in AD patients, but writing to dictating Kanji words was impaired. We classified the errors in the Kanji dictation task into four types to investigate the correlation between rCBF and the error type, as follows: non-response errors, phonologically plausible errors, non-phonologically plausible errors, and peripheral errors. Non-response errors, which indicated difficulty with retrieving Kanji graphic images, were the most frequent. When controlled for confounding factors, the number of non-response errors negatively correlated with rCBF in the left inferior parietal lobule, the posterior middle and inferior temporal gyri, and the posterior middle frontal gyrus. Thus, the impaired recall of Kanji in early Alzheimers disease is related to dysfunctional cortical activity, which appears to be predominant in the left frontal, parietal, and temporal regions.