Annual stability of the plasma Aß40/42 ratio and associated factors.

OBJECTIVE: The plasma Aß40/42 ratio is a biomarker of brain amyloidosis. However, the threshold difference between amyloid positivity and negativity is only 10-20% and fluctuates with circadian rhythms, aging, and APOE-ε4 during the decades of evolution of Alzheimer's disease. METHODS: Plasma Aß40 and Aß42 levels in 1472 participants aged between 19 and 93 years in the Iwaki Health Promotion Project for 4 years were statistically analyzed. RESULTS: The means and standard deviations of annual inter-individual coefficients of variation were 5.3 ± 3.2% for Aß40, 7.8 ± 4.6% for Aß42, and 6.4 ± 4.1% for the Aß40/42 ratio. No significant age-dependent changes were observed in inter-individual coefficients of variation. Age-dependent increases in Aß42 levels were suppressed, whereas those in the Aß40/42 ratio were enhanced in APOE-ε4 carriers. The change points of Aß42, Aß40, and the Aß40/42 ratio were 36.4, 38.2, and 43.5 years, respectively. In the presence of APOE-ε4, the Aß40/42 ratio increased in middle-aged and elderly subjects while Aß42 levels decreased in elderly subjects. INTERPRETATION: Individual values for Aß40, Aß42, and the Aß40/42 ratio did not fluctuate annually or in an age-dependent manner. If the plasma Aß40/42 ratio changes by more than 14.7% (+2 standard deviations) relative to age- and APOE-ε4-adjusted normal annual fluctuations, other biomarkers also need to be examined.

Lipid Rafts Act as a Common Platform for Amyloid-ß Oligomer-Induced Alzheimer's Disease Pathology.

BACKGROUND: Amyloid-ß (Aß) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer's disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. OBJECTIVE: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. METHODS: Cellular and synaptosomal lipid rafts were prepared from the brains of Aß amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. RESULTS: Aß dimers, the cellular prion protein (PrPc), and Aß dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3ß, total tau, phosphorylated tau, and tau oligomers increased with Aß dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aß accumulation in the amyloid model mice. CONCLUSION: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

Age-Related Cognitive Decline and Prevalence of Mild Cognitive Impairment in the Iwaki Health Promotion Project.

BACKGROUND: The Iwaki Health Promotion Project (IHPP) is a community-based study for the prevention of lifestyle-related diseases and improvement of quality of life. OBJECTIVE: Between 2014 and 2017, a total of 4,442 Iwaki town residents from 19 to 93 years of age participated in annual surveys to clarify the natural course of age-related cognitive decline and mild cognitive impairment (MCI). METHODS: Modified OLD and SED-11Q questionnaires, MMSE, Logical Memory II, educational history, and APOE genotypes were examined at the first screening. MCI and dementia were diagnosed at the second examination by detailed neurological examination, CDR, and MRI, and followed for 3 years. Spline regression analyses based on a linear mixed model was adopted for statistical analysis. RESULTS: MMSE scores declined with age from 55 to 64 years. There was also interaction between levels of education and ages. At the second examination, 56 MCI and 5 dementia patients were identified. None of the MCI cases progressed to dementia during the 3 years. During follow-up examinations, 13 cases showed improved MMSE scores (0.95 point/year), 5 remained stable, and 7 deteriorated (-0.83 point/year). Five cases showed improved CDR-SOB scores (-0.28 point/year), 9 remained stable, and 6 deteriorated (0.3 point/year). CONCLUSION: IHPP revealed that age- and education-related cognitive decline began and advanced from 55 years of age. The prevalence of MCI and dementia was estimated to be 5.9%in the Iwaki town cohort over 60 yeas of age. About 30%of MCI cases showed progression of cognitive decline.

Quantitative Measurement of Cerebrospinal Fluid Amyloid-ß Species by Mass Spectrometry.

BACKGROUND: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-ß (Aß) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. OBJECTIVE: We validated the Aß1-38, Aß1-40, Aß1-42, and Aß1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. METHODS: CSF samples from 120 subjects [8 Alzheimer's disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer's disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aß species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aß1-40 and Aß1-42 levels were validated using ELISA. RESULTS: CSF levels in CU were 666±249 pmol/L in Aß1-38, 2199±725 pmol/L in Aß1-40, 153.7±79.7 pmol/L in Aß1-42, and 9.78±4.58 pmol/L in Aß1-43. The ratio of the amounts of Aß1-38, Aß1-40, Aß1-42, and Aß1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aß species. Both Aß1-40 and Aß1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aß1-38 or Aß1-40 levels between AD and CU. Aß1-42 and Aß1-43 levels were significantly lower, whereas the Aß1-38/1-42, Aß1-38/1-43, and Aß1-40/Aß1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aß species were adequate for clinical usage. CONCLUSION: A quantitative LC-MS/MS assay of CSF Aß species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.

Aging and APOE-ε4 are determinative factors of plasma Aß42 levels.

OBJECTIVE: The aim of this study was to confirm determinative factors for plasma Aß and its association with cognitive function. METHODS: Fasting plasma Aß40 and Aß42 levels were measured by ELISA in 1019 participants in the Iwaki Health Promotion Project. The relationships between plasma Aß and health-related items, including physical characteristics, cognitive function tests, blood chemistry, and APOE-ε4 genotype were analyzed. RESULTS: The plasma levels of Aß40 and Aß42, and Aß40/42 ratio were found to significantly increase with aging. The age-dependent increase in Aß42 level was significantly suppressed by APOE-ε4. Renal function was an associated factor for the plasma Aß40 level. The plasma Aß42 level and Aß40/42 ratio correlated with cognitive function. INTERPRETATION: Age and APOE-ε4 are major determinative factors of plasma levels of Aß42 and the Aß40/42 ratio. These factors are critical adjustment factors for the usage of plasma Aß as a biomarker of central nervous system amyloidosis.

An unusual case of chronic relapsing tetanus associated with mandibular osteomyelitis.

A 55-year-old man underwent radiation therapy due to malignant lymphoma of the neck. Eight years after the therapy he developed tetanus. It appears that the radiation therapy resulted in mandibular necrosis, and that this lesion may have been the infectious focus of tetanus. Treatment with penicillin G was very effective in the acute stage, and chronic administration of metronidazole prevented relapse of the disease. However in spite of injections of tetanus toxoid, symptoms of tetanus returned when the administration of metronidazole was discontinued because the infectious focus could not be completely removed. This is the first report of chronic relapsing tetanus associated with radiation-induced mandibular osteomyelitis, and demonstrates that tetanus can occur due to mandibular focus but the chronic administration of metronidazole can prevent relapse.