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.

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.

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.

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.

Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease.

BACKGROUND: To date, there is no accepted clinical diagnostic test for Parkinson disease (PD) that is based on biochemical analysis of blood or CSF. The discovery of mutations in the SNCA gene encoding α-synuclein in familial parkinsonism and the accumulation of α-synuclein in the PD brain suggested a critical role for this protein in PD etiology. METHODS: We investigated total and α-synuclein oligomers levels in CSF from patients clinically diagnosed with PD, progressive supranuclear palsy (PSP), or Alzheimer disease (AD), and age-matched controls, using ELISA developed in our laboratory. RESULTS: The levels of α-synuclein oligomers and oligomers/total-α-synuclein ratio in CSF were higher in the PD group (n = 32; p < 0.0001, Mann-Whitney U test) compared to the control group (n = 28). The area under the receiver operating characteristic curve (AUC) indicated a sensitivity of 75.0% and a specificity of 87.5%, with an AUC of 0.859 for increased CSF α-synuclein oligomers in clinically diagnosed PD cases. However, when the CSF oligomers/total-α-synuclein ratio was analyzed, it provided an even greater sensitivity of 89.3% and specificity of 90.6%, with an AUC of 0.948. In another cross-sectional pilot study, we confirmed that the levels of CSF α-synuclein oligomers were higher in patients with PD (n = 25) compared to patients with PSP (n = 18; p < 0.05) or AD (n = 35; p < 0.001) or control subjects (n = 43; p < 0.05). CONCLUSION: Our results demonstrate that levels of α-synuclein oligomers in CSF and the oligomers/total-α-synuclein ratio can be useful biomarkers for diagnosis and early detection of PD.

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.

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.

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.

[Adult Sandhoff disease presented as a motor neuron disease phenotype with slow progression].

A 35-year old Japanese male with adult Sandhoff disease was described, who was presented as a motor neuron disease phenotype with slow progression. At the age of 15, he first noticed weakness in his thigh. At the age of 28, his upper and lower motor neuron disturbances were disclosed. He was diagnosed as atypical amyotrophic lateral sclerosis. At the age of 34, a slight sensory disturbance appeared in the lower extremities. When he was admitted to our hospital, he displayed marked atrophy and weakness in his quadriceps femoris muscles, but no signs of mental deterioration and cerebellar ataxia. Because of the atypical course of motor neuron disease, hexosaminidase activity in peripheral leukocytes was determined. The assay of total hexosaminidase, hexosaminidase A and hexosaminidase B activities demonstrated low levels of these activities (7-15% of controls), leading the diagnosis of Sandoff disease. He was a member of non-consanguineous family, and the abnormal patterns of hexasaminidase activities were different between his father and mother. These data appear to show that he is a compound heterozygote in the locus of the hexosaminidase B gene. This is the first Japanese case of adult Sanhoff disease presented as a motor neuron disease phenotype.

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.

[A case of eosinophilic myositis proven by immunohistochemistry using antibodies against eosinophilic granule protein].

A 50-year-old man had been well until three months earlier, when he felt general fatigue, and cutaneous rash with itching. Thereafter a general muscular weakness developed and the patient could not walk for a month. Four weeks before referral to our hospital, he had high fever and could not role over in the bed. On admission, the patient was able to walk. He had no skin rash. Neurologically, he showed mild weakness in proximal muscles. Hematologic examination showed mild eosinophilia and serum creatine kinase was mildly elevated. Needle electromyogram revealed a diffuse myogenic pattern in extremities. Eosinophilic myositis was diagnosed by a biopsy of the left calf muscle showing mild infiltration of eosinophilis which was identified using antibodies against eosinophilic granule protein.

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.

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.

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.

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.