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.

Assessment of mental deterioration with the Cognitive Abilities Screening Instrument (CASI) and glucose hypometabolism in Alzheimer's disease: the Osaki-Tajiri Project.

The Cognitive Abilities Screening Instrument (CASI) is a screening test for dementia consisting of 9 domains. We investigated the relationships between CASI domain scores and cerebral glucose metabolism (CMRglc) as shown by positron emission tomography. Fifteen patients with very mild Alzheimer's disease (AD) and 15 with mild AD were studied using the [(18)F]fluoro-deoxyglucose method. The 9 CASI domains were classified into four clusters (recent memory, frontal cortex cluster, posterior cortex cluster, and orientation). Using the region of interest method, the recent memory cluster was correlated with the bilateral hippocampal CMRglc, the frontal cortex cluster was correlated with the bilateral anterior and right inferior frontal CMRglc, the posterior cortex cluster was correlated with the bilateral temporo-parieto-occipital and occipital CMRglc, and the orientation cluster was correlated with the left anterior frontal CMRglc (Spearman's correlations). The use of statistical parametric mapping showed that most CASI domains were correlated with CMRglc of the left frontal lobe, the temporal lobe, and the angular gyrus. These findings show that the mental dysfunction assessed using CASI in AD patients has a neurobiological basis.

Eicosapentaenoic acid inhibits voltage-gated sodium channels and invasiveness in prostate cancer cells.

BACKGROUND AND PURPOSE: The voltage-gated Na(+) channels (Na(v)) and their corresponding current (I(Na)) are involved in several cellular processes, crucial to metastasis of cancer cells. We investigated the effects of eicosapentaenoic (EPA), an omega-3 polyunsaturated fatty acid, on I(Na) and metastatic functions (cell proliferation, endocytosis and invasion) in human and rat prostate cancer cell lines (PC-3 and Mat-LyLu cells). EXPERIMENTAL APPROACH: The whole-cell voltage clamp technique and conventional/quantitative real-time reverse transcriptase polymerase chain reaction analysis were used. The presence of Na(v) proteins was shown by immunohistochemical methods. Alterations in the fatty acid composition of phospholipids after treatment with EPA and metastatic functions were also examined. KEY RESULTS: A transient inward Na(+) current (I(Na)), highly sensitive to tetrodotoxin, and Na(V) proteins were found in these cells. Expression of Na(V)1.6 and Na(V)1.7 transcripts (SCN8A and SCN9A) was predominant in PC-3 cells, while Na(V)1.7 transcript (SCN9A) was the major component in Mat-LyLu cells. Tetrodotoxin or synthetic small interfering RNA targeted for SCN8A and SCN9A inhibited metastatic functions (endocytosis and invasion), but failed to inhibit proliferation in PC-3 cells. Exposure to EPA produced a rapid and concentration-dependent suppression of I(Na). In cells chronically treated (up to 72h) with EPA, the EPA content of cell lipids increased time-dependently, while arachidonic acid content decreased. Treatment of PC-3 cells with EPA decreased levels of mRNA for SCN9A and SCN8A, cell proliferation, invasion and endocytosis. CONCLUSION AND IMPLICATIONS: Treatment with EPA inhibited I(Na) directly and also indirectly, by down-regulation of Na(v) mRNA expression in prostate cancer cells, thus inhibiting their metastatic potential.

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.

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.

Excitotoxic lesions of the rhinal cortex in the baboon differentially affect visual recognition memory, habit memory and spatial executive functions.

To specify the functional role of the rhinal cortex, baboons with bilateral excitotoxic lesions of the rhinal cortex (RH group) were tested on a series of computerized memory and learning tasks. Preoperatively, they were trained to and then tested on a delayed nonmatching-to-sample (DNMS) task with trial-unique stimuli. Postoperatively, this visual recognition memory task was given twice. As compared to a sham-operated group, the RH group showed good retention of rule learning and were unimpaired on the Delay memory subtest. Performance on the List Length memory subtest was, however, severely impaired at both postoperative evaluations, with a significant negative correlation between cognitive performance and neuronal loss in rhinal areas. Visual habit memory and spatial working memory were assessed postoperatively only, using a concurrent discrimination learning task and both a delayed-response task (with a two- and four-location choice) and a delayed alternation task, respectively. The RH group was unimpaired on the first two tasks and was even faster than the controls in learning the delayed-response task with four locations. Finally, most RH baboons failed to learn the delayed alternation task within the limits of testing. These results indicate that neuronal loss in the rhinal cortex is sufficient to impair visual recognition memory, and extend the implication of this area to spatial executive functions. Furthermore, the observation of impaired recognition memory and executive processes with preserved procedural memory and retrograde memory suggests that damage to the rhinal cortex probably participates in the cognitive deficits typical of the early stages of Alzheimer's disease.

Five-year retrospective changes in hippocampal atrophy and cognitive screening test performances in very mild Alzheimer's disease: the Tajiri Project.

The medial temporal lobe, especially the hippocampus, is important for normal cognitive function. especially for memory, and is the region with the earliest and most extensive pathological changes in Alzheimer's disease (AD). We investigated the atrophic changes of the hippocampus over a 5-year period and its relation to cognitive screening test performances in normal elderly subjects, those with very mild AD, and patients with AD. Fifty-seven elderly subjects without a moderate or greater degree of cerebrovascular disease as shown by MRI were randomly selected from the town of Tajiri. Thirty-three subjects with a clinical dementia rating (CDR) of 0 (normal), 18 CDR-0.5 (very mild AD) subjects, and six CDR-1&2 (AD) subjects underwent MRI and the Mini Mental State Examination (MMSE) twice during the period. Retrospective changes in the hippocampal width and the MMSE scores were evaluated. There were significant CDR group effects for the changes in the mean bilateral hippocampal widths and the MMSE scores. Normal subjects did not show cognitive decline, although there was a slight tendency for hippocampal atrophy. A significant and meaningful Spearman's correlation was noted between left hippocampal atrophy and the MMSE scores over the 5-year period for the CDR-0.5 group. These CDR-0.5 subjects met the MCI (mild cognitive impairment) criteria as proposed by the consensus paper. Findings suggested that normal elderly subjects maintain a high level of cognitive functions for at least 5 years, although hippocampal atrophy might occur. Atrophic change of the left hippocampus might be a good marker of the very early stage of AD.

Global intellectual deterioration in Alzheimer's disease and a reverse model of intellectual development: an applicability of the Binet scale.

Since intellectual deterioration in Alzheimer's disease (AD) might be considered to demonstrate a reverse of the intellectual development of children, we herein investigated the applicability of the Tanaka-Binet Intelligence scale (TB scale). This scale can assess the mental age (MA) and the lower-limit age (LLAge) values, and was reported to be correlated with the tasks determining Piaget's developmental stages of intelligence. Thirty AD patients and 30 age-matched normal control subjects were examined with the scale. We found that the mean MA values of the AD patients and controls were 97.4 and 150.3 months, respectively. In the control group, there were significant correlations between the MA and chronological age, and between the MA and years of education. In the AD patients, there was a significant correlation between the MA and the MMSE score. Regarding the LLAge for the AD patients, similar to the theory of Piaget, there was a tendency that they could be classified into three LLAge groups. We consider that the TB scale is useful in assessing the intellectual function in AD patients.

Cognitive function and frontal lobe atrophy in normal elderly adults: Implications for dementia not as aging-related disorders and the reserve hypothesis.

We examined the relations between cognitive function and age and education in the normal elderly population. As per the community-based stroke, dementia, and bed confinement prevention in the town of Tajiri, neuropsychological assessments, including the Cognitive Ability Screening Instrument (CASI), were performed for 99 randomly selected normal elderly subjects. We assessed the frontal function (working memory, word fluency, Trail-Making Tests, CASI subitems of list-generating fluency, attention, and concentration/mental manipulation), language function (proverbs, CASI subitem language), non-language function (the digit symbol test of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), CASI subitem visual construction), memory (Alzheimer's Disease Assessment Scale recall/recognition, story recall, CASI subitems short and long-term memory, the Rey-Osterrieth Complex Figure Test), and the global function (CASI subitems orientation and abstraction and judgment). We found that the only test affected by age was the digit symbol test of the WAIS-R. The effects of education were distributed among various tests. There was a significant correlation between age and the frontal lobe atrophy in the lower educated group. The present findings suggest that cognitive function is spared by the aging process itself and dementia should be considered as age-related, not aging-related disorders, and that education might have a protective effect on cognitive change, supporting the reserve hypothesis.

Hemispatial visual-searching impairment correlated with decreased contralateral parietal blood flow in Alzheimer disease.

BACKGROUND: Impairment of visuospatial attention in Alzheimer disease (AD) has not been fully investigated. Mendez et al reported that patients with AD showed hemispatial biases on visual search tasks. Parietal lobe involvement might be related to such impairment. The Picture Description Task is one of the most sensitive tests for detecting language disorders and might be also useful in assessing visual search. OBJECTIVE: The applicability of the Picture Description Task for evaluating hemispatial visual search impairment of AD was investigated, as well as whether the hemispheric difference in parietal blood flow is related to such impairment. METHODS: Thirty-four patients with AD and age-matched 16 normal subjects performed the Picture Description Task. The elements of the picture were divided into three portions: the right portions (five elements), the central portions (two elements), and the left portions (five elements), so as to assess the patients' hemispatial visual searching ability. Using single photon emission CT, the absolute regional cerebral blood flow (CBF) values at resting condition were calculated by the method of Kuhl et al. RESULTS: Fourteen patients with AD showed a decreased number of elements pointed out in the left portion of the picture, whereas 12 patients had decreased attention in the right portion. The remaining eight pointed only to the central portion. None of them showed hemispatial neglect on the figure copying tasks. The patients with decreased left spatial attention had lower CBF in the right parietal lobe, and vice versa. A significant negative (biologically meaningful) Spearman correlation was found between the right-left indices of the elements pointed out in the picture and the CBF values. CONCLUSIONS: The results suggest that the Picture Description Task is useful for assessing visual search, and impaired hemispatial visual search in AD is related to decreased contralateral parietal blood flow. The right-left asymmetry of the parietal CBF might be associated with hemispatial visual attention impairments in AD.

Elderly Japanese emigrants to Brazil before World War II: II. Prevalence of senile dementia.

BACKGROUND: We previously showed the prevalence of dementia in the town of Tajiri (Miyagi Prefecture, Japan), and found it to be 8.0%. The first population-based study on dementia in Brazil (Catanduva) disclosed the prevalence as being 7.1%. To evaluate the effects of environment on development of dementia, elderly Japanese immigrants living in Brazil were examined. Brazil is the country with the largest number of Japanese immigrants. METHODS: All immigrants aged 65 years and over from Miyagi Prefecture, living in the four cities of the São Paulo Metropolitan area were targeted (n = 192). We were able to examine 166 subjects (86.5%). The diagnosis of dementia was based on the DSM-IV with the severity assessed by the CDR (clinical dementia rating) scales. The cognitive ability screening instrument (CASI) was used for neuropsychological assessment. RESULTS: Thirteen subjects were diagnosed with dementia, CDR 1-3, the prevalence being 7.8%. Older subjects suffered more from dementia, and, paradoxically, the more highly educated subjects also suffered more. All the CASI items, except for long-term memory and visual construction, significantly deteriorated in the CDR 0.5 group compared with the CDR 0 group. COMMENTS: The prevalence of dementia was not thought to be affected by environmental factors. A paradoxically higher rate of dementia in the more educated subjects was probably due to the historical problems of the immigrants. Intact CASI item long-term memory in the CDR 0.5 group indicated that suspected dementia patients could maintain this function. This is the first epidemiological study on dementia in elderly Japanese immigrants in Brazil.

Depressive symptoms and associated factors in a cognitively normal elderly population: the Tajiri Project.

BACKGROUND AND OBJECTIVE: Since depression is one of the main problems of elderly subjects, it is important to examine the prevalence of this condition and to identify associated factors. METHODS: A total of 1525 cognitively normal subjects aged 65 years and over in the town of Tajiri, a typical agricultural town in Japan, were analysed. Their MMSE (mini-mental state examination) scores were 24 or over. Depressive state was assessed by Zung's SDS (self-rating depression scale) with a comprehensive interview to examine ADL, demographics and symptoms associated with illness, etc. The prevalence of depression was calculated. To determine the factors associated with depression, the t-test and the Chi-square test were used. To examine the relative strength of each factor, logistic regression analysis was performed. RESULTS: The ratio of the depressive subjects was 6.4%, lower than those of previous reports, probably due to the effect of excluding dementia subjects. The ratio for older females aged 80 years and over was 14.3%, which was significantly higher than that of the males. Among socio-demographic factors, sex, age, number of children and perception of economic status, were significantly related. For health status and ADL, such factors as perception of health and medical history of heart disease and rheumatism were related. For familial and social status, factors such as daily activity and several conversation abilities were related. The logistic regression analysis indicated that perception of health and daily activity were associated. CONCLUSIONS: In this study, we isolated some factors related to depression in a cognitively normal population. Knowledge of such factors is important for appropriate mental care of aged subjects.

Elderly Japanese emigrants to Brazil before World War II: I. Clinical profiles based on specific historical background.

OBJECTIVE: To research the demographic and clinical profiles of elderly Japanese emigrants, who arrived in Brazil before World War II, in order to give them appropriate psychogeriatric care. DESIGN: Elderly Japanese immigrants aged 65 years and over, belonging to the Miyagi Association in the São Paulo Metropolitan Area, were targeted. They emigrated from Miyagi Prefecture to Brazil and are now living in the area. We were able to interview 166 respondents. All data were gathered using standardized interview methods covering (a) free interview about the immigration history, (b) demographics, and (c) physical status. RESULTS: Through the free interview, we found their immigration histories, which affected their clinical profiles. The mean age and educational level were 77.5 years and 6.3 years, respectively. Sixty per cent of them immigrated when they were younger than 14. Ninety-four per cent of them still keep Japanese nationality. Fifty-seven per cent of them usually use Japanese, while 10% of them use Portuguese. Although their emigration histories were hard, 76% of them perceived their health as being excellent or relatively good. The percentages of subjects with histories of disease were hypertension, 52.5%; cardiac disease, 20.8%; diabetes mellitus, 24.2%; and hyperlipidemia, 25.0%, which were affected by the Brazilian environment. CONCLUSION: The elderly Japanese who emigrated to Brazil before World War II have a unique historical and demographic background. Their clinical profiles cannot be fully understood without knowing their histories. They definitely need high quality international psychogeriatric care.

Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer's disease: a PET/MRI correlative study.

OBJECTIVES: Hippocampal atrophy and hypometabolism in the posterior association neocortex are two well known features of Alzheimer's disease. A correlation between these two features was reported twice previously, suggesting intriguing relations. This question has been reassessed, this time controlling for severity of dementia as well as assessing each side of the brain separately and using a voxel based image analysis in addition to the previously employed regions of interest (ROIs). PATIENTS AND METHODS: Eleven patients were studied with probable Alzheimer's disease and mild to moderate dementia in whom both volume MRI and PET assessed cerebral glucose consumption (CMRGlc) were available. Hypothesis driven correlations between hippocampal width (an index of atrophy) and CMRGlc were performed for two posterior association regions, the superior temporal and the inferior parietal (angular gyrus) cortices, using ROIs set separately for each hemisphere. To confirm significant correlations from the ROIs approach, if any, and to assess their specificity for the posterior association neocortex, CMRGlc image voxel based analysis of correlations with hippocampal width was then carried out. RESULTS: There was a significant correlation, in the positive-neurobiologically expected-direction, between right hippocampal width and right angular gyrus metabolism (p< 0.01, Spearman), which remained significant with Kendall partial correlation controlling for dementia severity (estimated by mini mental state scores). Statistical non-parametric mapping (SnPM) confirmed this correlation (p< 0.025), and showed a single additional correlation in the right middle temporal gyrus (p< 0.005), which is also part of the posterior association cortex. CONCLUSION: The findings with both ROIs and voxel based mapping replicate earlier reports of a relation between hippocampal atrophy and ipsilateral association cortex hypometabolism in Alzheimer's disease, and for the first time document that this relation is both region specific and independent of the dementing process itself. Why the correlation was significant only for the right hemisphere is unclear but may be related to the limited sample. Hippocampal-neocortical disconnection due to early and severe medial temporal lobe pathology may at least partly explain the posterior association cortex hypometabolism found in Alzheimer's disease.

A 5-year retrospective examination of cognitive screening test stages in normal older adults and patients with Alzheimer's disease: the Tajiri project.

One conception of aging and cognitive deterioration is that cognitive decline becomes common with age, and dementia may be regarded as one extreme of the continuum. An alternative conception is that the cognitive process is spared by the aging process itself and that cognitive functioning of normal older adults and those with slight cognitive impairment, a CDR (Clinical Dementia Rating) score of 0.5 (suspected dementia), should be different. We examined changes in the screening test performances of 170 older adults over a 5-year period and found the following: (a) The CDR 0 (normal) participants did not show remarkable changes even in the older groups and (b) the subitems of orientation, memory, and so forth were useful for distinguishing normal older adults from early Alzheimer's disease patients. The results support the idea that dementia is better conceptualized as an age-related than as an "aging-related" disorder and that a CDR score of 0.5 should be considered very mild Alzheimer's disease.

Impact of immediate cerebral angiography for in-hospital cerebral thromboembolism after cardiovascular surgery.

OBJECTIVES: Postoperative stroke remains a serious problem in cardiovascular surgery. We studied the role of cerebral angiography in postcardiotomy stroke. METHODS: We retrospectively analyzed 5 in-hospital patients with stroke due to cerebral thromboembolism after cardiovascular surgery. RESULTS: The incidence of in-hospital cerebral thromboembolism was 0.5%, involving 5 patients among 913 adults undergoing cardiovascular operations. In-hospital cerebral thromboembolism occurred 3 to 9 days (average: 7 +/- 2 days) after surgery. Causes of cerebral thromboembolism were chronic atrial fibrillation in 1, transient atrial fibrillation in 2, artificial valve in 1, and intracranial arterial stenosis in 1. Immediate cerebral angiography, after exclusion of intracranial hemorrhage and complete cerebral infarction by computed tomography, revealed cerebral embolism in 3 and cerebral thrombosis in 2 with occlusion or stenosis of intracranial arteries. Local intraarterial administration of a thrombolytic agent was done in the 3 patients with cerebral embolism and occluded arteries were recanalized. Fibrinolysis was not done in 2 because of recanalized arteries or sufficient peripheral blood supply through collateral feeders. No patients exhibited rebleeding into the pericardial space or wound bleeding. All patients survived with moderate or full functional recovery. CONCLUSION: Immediate cerebral angiography with/without local thrombolysis may improve functional outcome and survival in patients with postcardiotomy cerebral thromboembolism.

Autoimmune neutropenia in pregnant women causing neonatal neutropenia.

Autoimmune neutropenia (AIN) can occur during pregnancy. However, neonatal neutropenia occurring in an infant born to a mother with AIN has only rarely been documented. Recently, we have experienced two cases of AIN during pregnancy, both of which caused severe yet transient neonatal neutropenia (< 0.3 x 10(9)/l), probably as a result of transplacental maternal anti-neutrophil autoantibodies. The anti-neutrophil antibodies seemed to be against antigens other than NA1/NA2 because the autoantibodies did not bind to neutrophils of specific NA types selectively in the granulocyte indirect immunofluorescence test. Although AIN is a relatively uncommon disease, neonatal neutropenia caused by maternal AIN may not be quite as rare.

Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria.

The properties of 9 delta-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathione-affinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder.