Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region.

BACKGROUND: There is growing awareness of the coexistence of Alzheimer's disease and cerebrovascular disease (AD+CVD), however, due to lack of well-defined criteria and treatment guidelines AD+CVD may be underdiagnosed in Asia. METHODS: Sixteen dementia specialists from nine Asia Pacific countries completed a survey in September 2014 and met in November 2014 to review the epidemiology, diagnosis and treatment of AD+CVD in Asia. A consensus was reached by discussion, with evidence provided by published studies when available. RESULTS: AD accounts for up to 60% and AD+CVD accounts for 10-20% of all dementia cases in Asia. The reasons for underdiagnosis of AD+CVD include lack of awareness as a result of a lack of diagnostic criteria, misdiagnosis as vascular dementia or AD, lack of diagnostic facilities, resource constraints and cost of investigations. There is variability in the tools used to diagnose AD+CVD in clinical practice. Diagnosis of AD+CVD should be performed in a stepwise manner of clinical evaluation followed by neuroimaging. Dementia patients should be assessed for cognition, behavioural and psychological symptoms, functional staging and instrumental activities of daily living. Neuroimaging should be performed using computed tomography or magnetic resonance imaging. The treatment goals are to stabilize or slow progression as well as to reduce behavioural and psychological symptoms, improve quality of life and reduce disease burden. First-line therapy is usually an acetylcholinesterase inhibitor such as donepezil. CONCLUSION: AD+CVD is likely to be under-recognised in Asia. Further research is needed to establish the true prevalence of this treatable and potentially preventable disease.

Carnosine and its (S)-Trolox™ derivative protect animals against oxidative stress.

The novel synthetic derivative of carnosine, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-ß-alanyl-L-histidine (S-Trolox™-Carnosine, STC) increases the resistance of rats to experimental acute hypobaric hypoxia (AHH) thus protecting brain from the oxidative damage. This effect is accompanied by better preservation of the acquired skills in Morris water maze possibly by increasing efficiency of the brain antioxidant system. In addition, STC caused an increase in life span of both male and female fruit fly Drosophila melanogaster whereas carnosine increased life span only in male fruit flies. The results indicate that development of the drug based on STC could be beneficial in neurology and gerontology.

Biological activity of novel synthetic derivatives of carnosine.

Two novel derivatives of carnosine--(S)-trolox-L-carnosine (STC) and (R)-trolox-L-carnosine (RTC) are characterized in terms of their antioxidant and membrane-stabilizing activities as well as their resistance to serum carnosinase. STC and RTC were synthesized by N-acylation of L-carnosine with (S)- and (R)-trolox, respectively. STC and RTC were found to react more efficiently with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and protect serum lipoproteins from Fe(2+)-induced oxidation more successfully than carnosine and trolox. At the same time, STC, RTC and trolox suppressed oxidative hemolysis of red blood cells (RBC) less efficiently than carnosine taken in the same concentration. When oxidative stress was induced in suspension of cerebellum granule cells by their incubation with N-methyl-D-aspartate (NMDA), or hydrogen peroxide (H(2)O(2)), both STC and RTC more efficiently decreased accumulation of reactive oxygen species (ROS) than carnosine and trolox. Both STC and RTC were resistant toward hydrolytic degradation by human serum carnosinase. STC and RTC were concluded to demonstrate higher antioxidant capacity and better ability to prevent cerebellar neurons from ROS accumulation than their precursors, carnosine and trolox.

Prevalence and cognitive performances of vascular cognitive impairment no dementia in Japan: the Osaki-Tajiri Project.

Prevalence, magnetic resonance imaging (MRI) findings, cognitive function and depression are four major aspects of vascular cognitive impairment no dementia (vascular CIND). We performed a community-based study to examine these using 497 community-residents aged 65 years or older. Vascular CIND was defined as a clinical dementia rating (CDR) 0.5 with cerebrovascular disease. Several neuropsychological tests were performed, including MMSE, Geriatric Depression Scale (GDS), and Trail Making Test (TMT). Cerebrovascular disease and white matter lesions were visually assessed using MRI. Prevalence of vascular CIND, localization of cerebrovascular disease, and the relationships amongst MRI findings, white matter lesions, cognitive impairment and depression were analyzed. The prevalence of vascular CIND was 8.5% amongst the total population, corresponding to the rate being 37.2% amongst the CDR 0.5 participants. Compared with the CDR 0, the CDR 0.5 group had more subjects with strategic cerebrovascular disease in the thalamus, etc. No effects of cerebrovascular disease on MMSE and GDS scores were found, but the CDR 0.5/strategic cerebrovascular disease group showed impaired TMT-B scores. In the CDR 0 group, only anterior periventricular hyperintensity was associated with TMT-A score independent of cerebrovascular disease. A vascular CIND population was identified, and executive dysfunction in this population is probably based on an impaired fronto-subcortical circuit.

Behavioral and psychological symptoms assessed with the BEHAVE-AD-FW are differentially associated with cognitive dysfunction in Alzheimer's disease.

To assess the possible neurological basis of behavioral and psychological symptoms of dementia (BPSD), the relationships between BPSD and cognitive function were evaluated in 40 patients with Alzheimer's disease (AD). BPSD was assessed using the Behavioral Pathology in Alzheimer's Disease Frequency Weighted Severity Scale (BEHAVE-AD-FW) for behavioral symptoms and psychological symptoms separately, and cognitive function was also assessed using the Cognitive Abilities Screening Instrument (CASI). We found that only behavioral symptoms were associated with cognitive function based on the CASI total score and the score for the CASI attention domain. Administration of risperidone, an atypical anti-psychotic drug, for one month, improved the behavioral symptoms and the scores for the CASI attention and orientation domains. Our data suggest that BPSD in AD may reflect two largely independent pathophysiological processes: one associated with behavioral symptoms partly overlapping with attention, and the other associated with psychological symptoms predominantly unrelated to cognitive function.

Overexpression of AML1 renders a T hybridoma resistant to T cell receptor-mediated apoptosis.

The AML1 gene, which encodes the DNA binding subunit of the heterodimeric transcription factor, PEBP2/CBF, is involved in several types of chromosomal translocations associated with human acute myeloid leukemia, and has been shown by gene targeting to be essential for the development of definitive hematopoiesis in the murine fetal liver. In addition, the gene is expressed abundantly in T lymphocytes and has been implicated in T cell specific gene expression. In the present study we examined the function of AML1 in T cell receptor (TCR)-mediated, Fas/Fas-ligand dependent apoptosis of a T hybridoma line, DO11.10. Several independent cell clones overexpressing the AML1 protein were isolated by transfecting AML1 cDNA into these cells. These clones possessed an increased level of PEBP2/CBF DNA binding activity and were found to be resistant to apoptosis induced by anti-CD3 antibody treatment. Northern blot analysis revealed that induction of the Fas-ligand transcript was markedly suppressed in the anti-CD3 treated clones. Instead, expression of IL-2 receptor alpha subunit (IL-2R alpha), which is a manifestation of proliferative TCR signaling, was induced. This was in contrast to the parental, anti-CD3 treated DO11.10 cells where induction of Fas-ligand but not of IL-2R alpha was observed. Resistance of the AML1 overexpressing cell clones to TCR-mediated apoptosis is most likely attributable to the lack of Fas-ligand induction, since simultaneous treatment with anti-CD3 and anti-Fas antibodies caused apoptosis of the clones. The overall results suggest that the AML1 protein may play a pivotal role in switching TCR signaling between apoptosis and cell proliferation in T lymphocytes.

Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria.

The molecular defect of uroporphyrinogen decarboxylase (UROD) was examined in a patient with mild hepatoerythropoietic porphyria. To elucidate the UROD defect, we cloned UROD cDNAs from EBV-transformed lymphoblastoid cells of the proband using reverse transcriptase-polymerase chain reaction. Nucleotide sequence analysis of the cloned UROD cDNAs revealed two separate missense mutations, each occurring in a separate allele. One mutation was a Val134-->Gln transition, and was due to three sequential point mutations (T417G418T419-->CCA); the other mutation was a His220-->Pro transition (A677-->C). UROD phenotype studies demonstrated that the TGT-->CCA mutation was inherited from the father, and the A-->C mutation was inherited from the mother. In contrast to the null activity previously described for a mutant UROD from a patient with familial porphyria cutanea tarda, these mutant URODs had subnormal but substantial enzyme activities, when expressed in Chinese hamster ovary cells. This is the first demonstration of a mutation caused by three sequential base substitutions.

Striatal dopamine metabolism correlated with frontotemporal glucose utilization in Alzheimer's disease: a double-tracer PET study.

We previously found that the rate of [l8F]6-fluoro-L-dopa (FDOPA) uptake into the striatum (the Ki value) in Alzheimer's disease (AD) correlated with cognitive function. Patients with wandering behavior had an increased level of D2 dopamine receptors. Decreased cerebral glucose utilization (CMRglc) in the parietal and temporo-parieto-occipital region is a well-known PET finding in AD. We investigated the relationship between the Ki value and regional CMRglc (rCMRglc) with reference to cognitive impairment and wandering behavior. We studied 10 AD patients with moderately severe dementia. Using PET and the FDOPA and [18F]-fluoro-deoxyglucose techniques, the Ki value and rCMRglc in 10 regions in each hemisphere were measured. The Ki value was found to correlate with mean cortical rCMRglc. The rCMRglc of the anterior frontal, inferior frontal, and temporal lobes correlated with the Ki value; the patients with wandering behavior had lower values. Multiple regression analysis showed that the Mini-Mental State Examination score was significantly explained by the Ki value, the rCMRglc of the temporal lobe, and the rCMRglc of the parietal lobe. There is probably a functional neural network between the striatum and the frontal and temporal lobes in AD. We consider this network important, not only in cognitive impairment but also in abnormal wandering behavior.

An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.

Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondriai electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.

An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.

Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondrial electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.

Novel acyl-CoA:cholesterol acyltransferase inhibitors. Synthesis and biological activity of 3-quinolylurea derivatives.

A series of 3-quinolylurea derivatives (1) was synthesized and evaluated for acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity. For in vitro studies, the most potent inhibitory activity was found in derivatives having substituents at the 6,7- or 6,8-positions and an ortho-substituted phenyl group at the 4-position of quinoline ring. The 2,4-difluorophenyl group appeared to be the optimum N'-substituent of the urea moiety. The IC50 values of compounds 52-54 and 59 were in the nanomolar order. Plasma cholesterol-lowering activity of compounds 50, 52, and 54 was observed at less than 1 mg/kg/day in cholesterol-fed rats. Compound 52 was also hypocholesterolemic in hamsters fed a diet without loading cholesterol.

Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents.

In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72,107), a series of 5-[4-(2- or 4-azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabetic KKA(y) mice. Replacement of the 2-pyridyl moiety of pioglitazone by a 2- or 4-oxazolyl or a 2- or 4-thiazolyl moiety greatly enhanced in vivo potency. The corresponding 5-benzylidene-type compounds, in which a methine was used as a linker between the benzene ring and the thiazolidinedione ring, also had potent biological activity. Among the compounds synthesized, 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4- thiazolidinedione (18) exhibited the most potent activity, more than 100 times that of pioglitazone. The synthesis and structure-activity relationships for this novel series of derivatives are detailed.

Histamine H(1) receptors in patients with Alzheimer's disease assessed by positron emission tomography.

Cerebral histamine H(1) receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients with Alzheimer's disease by positron emission tomography and [11C]doxepin, a radioligand for H(1) receptors. The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis, and were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H(1) receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer's disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer's disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer's disease brain. However, the difference in the binding potential (total concentration of receptor/equilibrium dissociation constant) between the Alzheimer's disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer's disease was greater than the rate of decrease in the cerebral blood flow. This study reveals the predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer's disease. This study suggests that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits of Alzheimer's disease patients.

Measurement of D2 dopamine receptor-specific carbon-11-YM-09151-2 binding in the canine brain by PET: importance of partial volume correction.

Carbon-11-YM-09151-2 binds highly selectively to D2 dopamine receptors in the brain. Using this ligand, D2 dopamine receptor density (Bmax) and affinity (Kd) in canine striatum were measured. After administering various doses of the ligand in nine experiments, regional uptake was followed by repeated PET scanning for up to 80 min. D2 dopamine receptor specific binding at equilibrium was defined as striatal minus occipital activity after partial volume correction. Bmax and Kd were estimated by Scatchard analysis to be 40.3 pmole/ml of tissue and 22.9 nM, respectively. When a low mass dose of the ligand was administered, the bound-to-free ligand ratio in the striatum at equilibrium was consistent with the Bmax/Kd value obtained from the Scatchard analysis. The present study demonstrates the importance of partial volume correction and the Bmax/Kd measurement in a single PET study with carbon-11-YM-09151-2.

Sleep disturbance in elderly patients with cognitive impairment, decreased daily activity and periventricular white matter lesions.

We investigated how sleep disturbance is correlated with brain lesions, cognitive impairment and decreased daily activity (ADL). Two hundred and four chronically ill patients including patients with vascular dementia were classified into eight groups based on cognitive function, ADL and grades of PVL (periventricular lucency) as shown by computerized tomography. Visual monitoring of the sleep/wake state was performed hourly for 14 consecutive days and the daytime sleep hours and the nighttime sleep hours were determined based on detected disturbances in the sleep/wake pattern. Whether any specific infarcted regions were correlated with sleep disturbance was also evaluated. We found that daytime sleep hours were increased and nighttime sleep hours were decreased by three single factors: cognitive impairment, decreased ADL and the severe grade of PVL. As for an interactive effect of the two factors, daytime sleep hours were increased by dementia with decreased ADL (independent of PVL) and increased by decreased ADL with the severe grade of PVL (independent of dementia). Although three factors affected sleep independently, ADL has an interactive effect on sleep with dementia and with PVL. No specific cortical regions related to sleep disturbance were found.

Disturbance in daily sleep/wake patterns in patients with cognitive impairment and decreased daily activity.

The sleep/wake patterns of 121 chronically ill, mentally and physically handicapped patients were visually monitored hourly for 14 consecutive days. Four types of sleep/wake patterns were found. In order to investigate how cognitive and physical functions correlated with sleep disorders, patients were classified based on a scale of mental function and the grading of daily activity. The percent of total sleep hours and the sleep rating, showing disturbances in sleep/wake pattern, were evaluated. We found a high degree of individuality in sleep/wake patterns. Sleep disturbance was associated with daily activity as well as with cognitive impairment. This monitoring system provides medical personnel with valuable information for clinical management.

A cutaneous agranular CD2- CD4+ CD56+ "lymphoma": report of two cases and review of the literature.

We report 2 cases of agranular CD2- CD4+ CD56+ non-Hodgkin lymphoma in which skin seemed to be the primary site. A 21-year-old woman's initial symptom was a skin nodule on the right cheek. She also had tumors in the nasopharynx, and the bone marrow subsequently became involved. No lymphadenopathy was present. She experienced complete remission after dose-intensified therapy with cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone (CHOP), but the disease relapsed in the central nervous system 6 months later. An 81-year-old man experienced an 11-month history of skin nodules in the left forearm. On admission, he had a bone marrow infiltration of lymphoma cells. He died of pneumonia during chemotherapy. The malignant cells of the 2 patients had similar morphologic features, with a monocytoid nucleus and no cytoplasmic granules. The cells in both cases showed a unique phenotype: CD2-, CD3-, CD4+, CD8-, CD13-, CD14-, CD34-, CD16-, CD56+, CD57-, HLA-DR-positive. Staining for peroxidase and alpha-naphthyl butyrate esterase was negative. The T-cell receptor beta, gamma, delta, IgH, kappa, lambda genes were of germ line configurations. The DNA of Epstein-Barr virus was not detected from the bone marrow cells by polymerase chain reaction. Only 3 other cases with similar phenotypes have been reported; all had skin lesions. Although the origin of these cells remains unknown, we propose that this is a distinct clinicopathologic entity.

Functional analysis of cDNAs for two types of human heme oxygenase and evidence for their separate regulation.

We cloned a cDNA coding for a putative human heme oxygenase isozyme, designated type 2 (HO-2), and analyzed its function by transient expression assays. HeLa cells transfected with either HO-2 cDNAs or a cDNA coding for authentic heme oxygenase (HO-1) expressed the activity of heme oxygenase, although no activity was detected in the mock transfected cells. Using specific anti-HO-1 antibody, we showed that expression of a HO-1 cDNA resulted in the increase in its protein levels, but HO-1 protein was not detectable in the cells expressing HO-2 cDNAs. We thus confirmed the functional identity of HO-1 and HO-2. Then, we analyzed their expression in an erythroid cell line, YN-1-0-A. Treatment with hemin or by heat shock (42 degrees C) led to a remarkable increase in the HO-1 mRNA levels, while HO-2 mRNA expression was not induced at all, suggesting that they are under separate regulation.

Cutaneous stimulation regulates blood flow in cerebral cortex in anesthetized rats.

The effect of noxious or innocuous mechanical stimulation of cutaneous areas (face, forelimb and paw, back, hindlimb and paw) on cerebral blood flow in cortex was examined with laser Doppler flowmetry in anesthetized rats. Pinching of the face, forepaw and hindpaw for 15 s produced significant increases of systemic blood pressure and of cortical blood flow, whereas pinching of the back or brushing of any cutaneous area produced no significant changes in either parameter. Following spinal transection at the first thoracic level, the blood pressure response to forepaw pinching was suppressed, whereas the increase in cortical blood flow still took place. Thus the results suggest that the increase in cortical blood flow following cutaneous noxious stimulation is, in part at least, independent of changes in blood pressure and of any concomitant vasodilatation.

Age-dependent decrease in histamine H1 receptor in human brains revealed by PET.

Age-related changes in histamine H1 receptors were studied using [11C]pyrilamine or [11C]doxepin by positron emission tomography (PET). The frontal, parietal and temporal cortices showed age-related decreases in binding of approximately 13% per decade. In contrast, the thalamus showed no apparent decrease in binding during normal ageing because of its higher nonspecific binding. Post mortem studies also indicated that the nonspecific binding of [3H]pyrilamine in the thalamus was approximately 112% higher than that in the cortex. However, no significant decrease in histamine H1 receptors with age was observed by in vitro binding assays of autopsied human frontal cortex. Possible reasons are given for the larger effects of age observed in the PET study than in the in vitro post mortem binding study.