Decreased regional cerebral blood flow in patients with diphenylarsinic acid intoxication.

BACKGROUND AND PURPOSE: Diphenylarsinic acid (DPAA) intoxication caused by drinking contaminated well water was found in Kamisu, Japan. The symptoms indicated cerebellar-brainstem and temporo-occipital involvement. However, it remains unclear how it affects the human brain. To elucidate the effect of DPAA on the human brain, we analyzed cerebral blood flow (CBF) data after the drinking of DPAA-contaminated water was stopped and investigated the correlation between DPAA exposure level and CBF by single-photon emission computed tomography (CBF-SPECT). METHODS: The DPAA-exposed inhabitants (n = 78) were divided into 35 symptomatic and 43 asymptomatic subjects and compared with 38 healthy controls. The DPAA concentration in nails or hair and well water was measured using a high-performance liquid chromatography system and coupled plasma mass spectrometry after adequate extraction treatment. CBF-SPECT data, obtained within 1 year after the drinking of contaminated well water was stopped, were analyzed by statistical parametric mapping. We also examined the relationship between variations in CBF-SPECT signals and variations in DPAA concentrations in the hair or nails of the subjects. RESULTS: Compared with control subjects, CBF in symptomatic DPAA-exposed subjects was significantly lower in the occipital lobe, including the cuneus and inferior occipital gyri. The DPAA concentration in the nails or hair of subjects was inversely and significantly related to their CBF. CONCLUSION: These data suggest that CBF-SPECT may be useful as a clinical marker to infer the effect of accumulated DPAA on the brain.

Nationwide survey on cerebral amyloid angiopathy in Japan.

BACKGROUND AND PURPOSE: A nationwide survey was conducted to understand the epidemiology of cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-related ICH) and cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri) in Japan. METHODS: To estimate the total number and clinical features of patients with CAA-related ICH and CAA-ri between January 2012 and December 2014 and to analyze their clinical features, questionnaires were sent to randomly selected hospitals in Japan. RESULTS: In the first survey, 2348 of 4657 departments responded to the questionnaire (response rate 50.4%). The total numbers of reported patients with CAA-related ICH and CAA-ri were 1338 and 61, respectively, and their total numbers in Japan were estimated to be 5900 [95% confidence interval (CI) 4800-7100] and 170 (95% CI 110-220), respectively. The crude prevalence rates were 4.64 and 0.13 per 100 000 population, respectively. The clinical information of 474 patients with CAA-related ICH obtained in the second survey was as follows: (i) the average age of onset was 78.4 years; (ii) the prevalence increased with age; (iii) the disease was common in women; and (iv) hematoma most frequently occurred in the frontal lobe. Sixteen patients with CAA-ri for whom data were collected in the second survey had the following characteristics: (i) median age of onset was 75 years; (ii) cognitive impairment and headache were the most frequent initial manifestations; and (iii) focal neurological signs, such as motor paresis and visual disturbance, were frequently observed during the clinical course. CONCLUSIONS: The numbers of patients with CAA-related ICH and CAA-ri in Japan were estimated.

Sequential imaging analysis using MIBG scintigraphy revealed progressive degeneration of cardiac sympathetic nerve in Parkinson's disease.

BACKGROUND: Metaiodobenzylguanidine (MIBG) cardiac scintigraphy was used to differentiate Parkinson's disease (PD) with Lewy body pathology from other degenerative parkinsonisms. MIBG cardiac scintigraphy demonstrates the extent of degeneration of myocardial post-ganglionic sympathetic nerves in patients with PD. Because of its specificity for Lewy body (LB) pathology, MIBG scan might also be useful biomarker for the neurodegeneration attributed to PD. To estimate the utility of the imaging technique as a biomarker, we conducted sequential imaging analysis and power analysis. METHODS: Sixty-three patients who met the UK PD Society Brain Bank criteria were enrolled in this study. (123) I-MIBG myocardial scintigraphy was performed on all subjects, and the heart to mediastinum (H/M) ratio was calculated. A second imaging session was carried out after a mean interval of 268 days. RESULTS: Sequential imaging revealed a 2.9% decline of the H/M ratio from the baseline to the follow-up image, which reached statistical significance, but the power analysis showed that a relatively large number of patients would be required to demonstrate the neuroprotective effects of any therapy. CONCLUSIONS: Sequential imaging using (123) I-MIBG myocardial scintigraphy revealed progressive degeneration of the cardiac sympathetic nerve in 63 patients with PD. Although careful elimination of other disease conditions that damage the cardiac sympathetic nerve system is necessary, (123) I-MIBG myocardial scintigraphy may be a useful addition to clinical trials that intend to prove neuroprotection among patients with PD.

A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: The present study aims to clarify the clinical features of non-hypertensive cerebral amyloid angiopathy-related lobar intracerebral hemorrhage (CAA-L-ICH). METHODS: We investigated clinical, laboratory, and neuroimaging findings in 41 patients (30, women; 11, men) with pathologically supported CAA-L-ICH from 303 non-hypertensive Japanese patients aged >OR=55, identified via a nationwide survey as symptomatic CAA-L-ICH. RESULTS: The mean age of patients at onset of CAA-L-ICH was 73.2 +/- 7.4 years; the number of patients increased with age. The corrected female-to-male ratio for the population was 2.2, with significant female predominance. At onset, 7.3% of patients received anti-platelet therapy. In brain imaging studies, the actual frequency of CAA-L-ICHs was higher in the frontal and parietal lobes; however, after correcting for the estimated cortical volume, the parietal lobe was found to be the most frequently affected. CAA-L-ICH recurred in 31.7% of patients during the average 35.3-month follow-up period. The mean interval between intracerebral hemorrhages (ICHs) was 11.3 months. The case fatality rate was 12.2% at 1 month and 19.5% at 12 months after initial ICH. In 97.1% of patients, neurosurgical procedures were performed without uncontrollable intraoperative or post-operative hemorrhage. CONCLUSIONS: Our study revealed the clinical features of non-hypertensive CAA-L-ICH, including its parietal predilection, which will require further study with a larger number of patients with different ethnic backgrounds.

Antibodies to amyloid beta protein (A beta) crossreact with glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

In the present study, we characterized the epitope of a monoclonal antibody against purified amyloid plaque cores (Am-3). By immunocytochemical experiments, Am-3 stained cerebrovascular and senile plaque amyloid in brain sections of patients with Alzheimer's disease (AD) in a similar manner to that of antibodies against amyloid beta-protein (A beta). By Western blotting experiments, Am-3 recognized only a 35 kDa protein, which was revealed to be glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and not A beta or beta amyloid precursor protein (beta PP). However, Am-3 recognized both GAPDH and purified native A beta in a dot-binding assay. Therefore, we concluded that Am-3 recognized both GAPDH and native A beta. Other monoclonal antibodies (6C6 and AmT-1) against the synthetic peptide corresponding to residues 1-28 of A beta also recognized these proteins. Because the amino acid sequences of these two proteins are not homologous, we propose that the crossreactivity between A beta and GAPDH is a consequence of their similar conformational epitopes. The possibility of crossreactions would complicate immunochemical and immunocytochemical studies of brain aging, AD and Down's syndrome. The implications of crossreactivity in developing immunological assays and in investigating the amyloid deposits of AD are discussed.

Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition.

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.

Prednisolone (30-60 mg/day) for diseases other than AD decreases amyloid beta-peptides in CSF.

The effect of corticosteroid on the concentration of amyloid beta-peptide (Abeta) in human CSF obtained from 16 patients without dementia treated with prednisolone (> or =30 mg daily) was studied. The concentrations of Abetax-40 and Abetax-42 in CSF decreased after treatment was started (p < 0.002). A moderate- or high-dose regimen of prednisolone decreases Abeta production or increases Abeta degradation in the human brain and deserves further study in AD.

Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation.

A patient with hereditary neuropathy presented with asymmetric distal weakness. On nerve biopsy, there was demyelination and onion-bulb formation, and molecular analysis revealed that the patient was heterozygous for an MPZ mutation. The patient improved with corticosteroid treatment.

Apolipoprotein E allele-dependent antioxidant activity in brains with Alzheimer's disease.

Thiobarbituric acid-reactive substances (TBARS), an index of lipid peroxidation, were assayed in postmortem brain. Basal TBARS levels were increased and oxidative stimulation produced more TBARS in AD relative to control brains. In addition, apolipoprotein E isoforms showed differing antioxidant activities, with E2 > E3 > E4, suggesting that the lowest antioxidant activity of E4 could contribute to its association with AD.

Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome.

In Down syndrome (DS) brain an early, selective accumulation of amyloid beta (Abeta) peptides ending at residue 42 (Abeta42) occurs. Whether this event depends on an altered processing of amyloid beta precursor protein (APP) or on defective clearance is uncertain. To investigate this issue, we measured Abeta species 40 and 42 in plasma from 61 patients with DS, 77 age-matched normal controls, and 55 mentally retarded subjects without chromosomal abnormalities. The Abeta 40 and 42 plasma levels were then correlated with apolipoprotein E (apoE) genotypes in all groups of cases, and with I. Q. and Mini Mental Status Examination values in DS subjects. Both Abeta species were significantly elevated in DS compared to control groups, and the extent of their increase reflects that expected from APP gene overexpression. Plasma levels of Abeta 40 and 42 did not correlate with apoE genotypes in DS and control cases, and with the extent of mental retardation in DS subjects. The results indicate that accumulation and clearance of plasma and cerebral Abeta are regulated by different and independent factors.

Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

Cessation of cerebral hemorrhage recurrence associated with corticosteroid treatment in a patient with cerebral amyloid angiopathy.

We report the case of a 65 year old female patient with biopsy-proven cerebral amyloid angiopathy (CAA). She experienced intracerebral hemorrhages 4 times during 23 days but these serious strokes did not recur after corticosteroid therapy was started and her condition greatly improved. Since high titers of antinuclear antibodies and elevated erythrocyte sedimentation rate were found in her serum, she may have an inflammatory disorder involving amyloid-laden cerebral vessels. This is the first report showing the usefulness ofcorticosteroid for the treatment of CAA-related cerebral hemorrhages. Additionally, the concentrations of Abeta40 and Abeta42 in the CSF of this patient decreased rapidly after the use of corticosteroid, and ultimately fell far below normal values.

Emergence of immunoreactivities for phosphorylated tau and amyloid-beta protein in chronic stage of fluid percussion injury in rat brain.

Head injury is one of the potential environmental factors in Alzheimer's disease (AD). To study the chronic stage of concussive brain injury, histological analyses were performed 2-6 months after right lateral fluid percussion (FP) brain injury (3.6-4.8 atm) in rats. Six months after injury, numerous normal-looking neurons in the telencephalon and brain stem were immunoreactive with either antibody to phosphorylated tau or with four antibodies to beta-amyloid protein. Neuronal counts in the cortices were gradually decreased after injury, up to 42% loss at 6 months after injury. These neuropathological changes suggest that this animal model could serve as a good animal model of neurodegenerative diseases such as AD.

Amyloid beta protein 1-42/43 (A beta 1-42/43) in cerebellar diffuse plaques: enzyme-linked immunosorbent assay and immunocytochemical study.

Diffuse plaques are immature and amorphous senile plaques and believed to be in the initial phase of plaque formation. In contrast to amyloid angiopathy and the plaque core amyloid, diffuse plaques failed to be purified in preserved forms from the brain. Here, we studied the diffuse plaques in the cerebellar region of the Alzheimer's disease brain based on immunocytochemistry and ELISA using two different monoclonal antibodies specifically recognizing the carboxyl termini of A beta molecules (BA27 for A beta 1-40 and BC05 for A beta 1-42/43). We found that the amount of A beta 1-40 was in proportion to the staining degree on amyloid angiopathy by immunohistochemistry. We found that A beta 1-42/43 comprised diffuse plaques as the major component in the cerebella of AD brains. Taking these findings into consideration, diffuse plaques, the earliest pathological change in the brain with AD, are concluded to be composed mainly of A beta 1-42/43, implicating the critical importance of this kind of A beta species deposition in the pathogenesis of AD.

Characterization of amyloid beta protein species in cerebral amyloid angiopathy of a squirrel monkey by immunocytochemistry and enzyme-linked immunosorbent assay.

We analyzed the composition of amyloid beta protein (A beta) species in cerebral amyloid angiopathy (CAA) of an aged squirrel monkey. Immunocytochemistry demonstrated that the cerebral cortex contained no lesions other than widespread CAA with A beta40 as its apparent major component. However, enzyme-linked immunosorbent assay revealed that A beta42(43) predominated over A beta40 in a formic acid-extracted cortical fraction. These findings suggest possible underestimation of A beta42(43) levels in some previous immunocytochemical investigations.

Abeta1-40 but not Abeta1-42 levels in cortex correlate with apolipoprotein E epsilon4 allele dosage in sporadic Alzheimer's disease.

Apolipoprotein E (ApoE) epsilon4 allele is established to be a risk factor for the development of late-onset Alzheimer's disease (AD) which is associated with increased frequency of senile plaques and extent of amyloid angiopathy. In a recent report, we demonstrated that ApoE epsilon4 dosage correlates with an increase in A beta1-40 but not A beta1-42/43-immunoreactive plaques. In the present study, we sought to confirm this relationship at a biochemical level by using a sensitive ELISA to measure the amounts of A beta1-42/43 and A beta1-40 in cerebral cortex in 36 cases of sporadic AD. We found that dosage of ApoE epsilon4 allele correlated significantly with cortical A beta1-40 levels, while levels of A beta1-42 showed no significant association with genotype. These results parallel our immunohistochemical findings and suggest that A beta1-40 may play a key role in the pathogenesis of late-onset sporadic AD.

Increased amyloid beta protein in the skin of patients with amyotrophic lateral sclerosis.

Distinct vascular and periadnexal immunoreactivity have been observed for amyloid b protein (Abeta) in skin from patients with amyotrophic lateral sclerosis (ALS). We used an enzyme-linked immunosorbent assay to make a more quantitative comparison of Abeta concentrations between ALS patients and controls. The insoluble fractions of skin samples from ALS patients contained significantly higher Abeta concentrations per milligram protein than those from controls. Various alterations in extracellular matrix components have been reported to occur in the skin of patients with ALS, and several matrix constituents have been shown to affect processing and aggregation of Abeta in human brain. Taking these previous findings together with those of the present study, our observations suggest that changes in extracellular matrix in skin of ALS patients may facilitate aggregation and deposition of Abeta.

Carboxyl end-specific monoclonal antibodies to amyloid beta protein (A beta) subtypes (A beta 40 and A beta 42(43)) differentiate A beta in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys.

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) in the brains of five aged (20-26 years old) cynomolgus monkeys were investigated immunohistochemically using two monoclonal antibodies (anti-A beta 40 (BA27) and anti-A beta 42(43) (BC05)) that can differentiate the carboxyl termini of amyloid beta protein (A beta) subtypes. In four of five animals, all types of SPs (i.e. diffuse, primitive, and classical plaques; DPs, PPs, and CPs, respectively) were identified by BC05. However, BA27 did not label DPs and stained only about one third of PPs and CPs, mainly labeling granular structures and cored portions, respectively. In CAA, lesions of cortical capillaries reacted to BC05 in four of five cases, but rarely and weakly to BA27 in two of five cases. On the other hand, lesions of parenchymal and meningeal arterioles were stained by both BA27 and BC05. These staining profiles of SPs in cynomolgus monkeys correspond well to those in humans, although there are two remarkable features in cynomolgus monkeys. First, BA27 stained PPs associated with granular structures. Secondly, capillary A beta reacted intensely to BC05 but only slightly to BA27. Despite these unique features, the results suggest that aged cynomolgus monkeys can be used to investigate the pathogenesis of A beta deposition in SPs and CAA.

Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population.

We compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin-converting enzyme (ACE) in 133 Japanese sporadic Alzheimer disease (AD) patients with 257 controls. The association between AD and ACE genotypes or alleles was found to be significant. The frequency of II genotypes was 1.4 times higher in AD than controls, while that of DD genotypes was only 0.4 times as high. The altered distribution of ACE alleles in patients with AD appeared to be independent of apolipoprotein E.