Cerebral white matter lesions and regional blood flow are associated with reduced cognitive function in early-stage cognitive impairment.

Background: Differences in the extent of cerebral white matter lesions (WML) and regional cerebral blood flow (rCBF) in early-stage cognitive impairment (ESCI) contribute to the prognosis of cognitive decline; however, it is unclear precisely how WML and rCBF affect cognitive decline in ESCI. Objective: We examined the association between WML, rCBF, and cognitive impairment in the ESCI, using path analysis to clarify how these variables affect each other. Methods: Eighty-three patients who consulted our memory clinic regarding memory loss were included in this study based on the Clinical Dementia Rating. Participants underwent the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging (MRI) for voxel-based morphometry analysis, and brain perfusion single-photon emission computed tomography (SPECT) for rCBF evaluation in cortical regions, using 3D stereotactic surface projection (3D-SSP) analysis. Results: Path analysis was performed on the MRI voxel-based morphometry and SPECT 3D-SSP data, showing a significant correlation between both and MMSE scores. In the most suitable model (GFI = 0.957), correlations were observed between lateral ventricular (LV-V) and periventricular WML (PvWML-V) volumes [standardized coefficient (SC) = 0.326, p = 0.005], LV-V and rCBF of the anterior cingulate gyrus (ACG-rCBF; SC = 0.395, p < 0.0001), and ACG-rCBF and PvWML-V (SC = 0.231, p = 0.041). Furthermore, a direct relationship between PvWML-V and MMSE scores was identified (SC = -0.238, p = 0.026). Conclusion: Significant interrelationships were observed among the LV-V, PvWML-V, and ACG-rCBF that directly affected the MMSE score in the ESCI. The mechanisms behind these interactions and the impact of PvWML-V on cognitive function require further investigation.

Proteomic profiling of intestinal epithelial-like cell-derived exosomes regulated by epigallocatechin gallate.

Exosomes are extracellular vesicles primarily responsible for intercellular communication, and they contain nucleic acids and proteins. Exosome secretion has been observed in the intestines, suggesting their physiological effects on the receptor cells of target tissues. It is possible that intestinal epithelial cells recognize food components as ligands, resulting in exosome secretion. However, research on intestine-derived exosomes regulated by food ingredients is limited. In this study, Caco-2 cells were utilized as an intestinal epithelial model for proteomic profiling. NanoLC-MS/MS analysis revealed the alteration of exosome properties by epigallocatechin gallate (EGCG) in differentiated Caco-2 cells. This natural polyphenol reduced both the number and size of secreted exosomes and altered the expression of exosomal proteins. The enriched proteins in exosomes were involved in immune response and cell proliferation. In contrast, those in the EGCG-treated group had distinctive functions in the maintenance of skin homeostasis. We also found variable expression of galectin-3-binding protein and fibronectin as molecular signatures in exosomes derived from EGCG-treated cells. These results could help elucidate the expression and mechanism of exosomal proteins related to food components.

Genome-Wide RNA Sequencing Analysis in Human Dermal Fibroblasts Exposed to Low-Dose Ultraviolet A Radiation.

Ultraviolet A (UVA) radiation can pass through the epidermis and reach the dermal skin layer, contributing to photoaging, DNA damage, and photocarcinogenesis in dermal fibroblasts. High-dose UVA exposure induces erythema, whereas low-dose, long-term UVA exposure causes skin damage and cell senescence. Biomarkers for evaluating damage caused by low-dose UVA in fibroblasts are lacking, making it difficult to develop therapeutic agents for skin aging and aging-associated diseases. We performed RNA-sequencing to investigate gene and pathway alterations in low-dose UVA-irradiated human skin-derived NB1RGB primary fibroblasts. Differentially expressed genes were identified and subjected to Gene Ontology and reactome pathway analysis, which revealed enrichment in genes in the senescence-associated secretory phenotype, apoptosis, respiratory electron transport, and transcriptional regulation by tumor suppressor p53 pathways. Insulin-like growth factor binding protein 7 (IGFBP7) showed the lowest p-value in RNA-sequencing analysis and was associated with the senescence-associated secretory phenotype. Protein-protein interaction analysis revealed that Fos proto-oncogene had a high-confidence network with IGFBP7 as transcription factor of the IGFBP7 gene among SASP hit genes, which were validated using RT-qPCR. Because of their high sensitivity to low-dose UVA radiation, Fos and IGFBP7 show potential as biomarkers for evaluating the effect of low-dose UVA radiation on dermal fibroblasts.

Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile.

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer's disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). OBJECTIVE: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. METHODS: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-ß protein (Aß)42, Aß40, Aß38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. RESULTS: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aß38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. CONCLUSION: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aß clearance.

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Cascade process mediated by left hippocampus and left superior frontal gyrus affects relationship between aging and cognitive dysfunction.

BACKGROUND: Cognitive function declines with age and has been shown to be associated with atrophy in some brain regions, including the prefrontal cortex. However, the details of the relationship between aging and cognitive dysfunction are not well understood. METHODS: Across a wide range of ages (24- to 85-years-old), this research measured the gray matter volume of structural magnetic resonance imaging data in 39 participants, while some brain regions were set as mediator variables to assess the cascade process between aging and cognitive dysfunction in a path analysis. RESULTS: Path analysis showed that age affected the left hippocampus, thereby directly affecting the left superior frontal gyrus. Furthermore, the gyrus directly affected higher order flexibility and maintenance abilities calculated as in the Wisconsin card sorting test, and the two abilities affected the assessment of general cognitive function. CONCLUSION: Our finding suggests that a cascade process mediated by the left hippocampus and left superior frontal gyrus is involved in the relationship between aging and cognitive dysfunction.

Case Report: Paraneoplastic Hashimoto's Encephalopathy Associated With Lymphomatosis Cerebri With Periodic Synchronous Discharges Resembling Creutzfeldt-Jakob Disease.

Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that presents with various clinical symptoms, including cognitive deterioration, convulsive seizures, and personality changes. HE is associated with thyroid autoimmunity; however, few cases have been reported to develop as paraneoplastic syndrome. Herein, we report the case of a 73-year-old woman with onset of rapidly progressive dementia. Brain magnetic resonance imaging showed diffuse T2 hyperintensity areas involving the bilateral cerebral white matter, right midbrain tegmental area, left cerebral peduncle, and right middle cerebellar peduncle without clear diffusion hyperintensities and gadolinium enhancement. Her neurological symptoms worsened rapidly, and she presented with the apallic syndrome. Electroencephalogram showed periodic synchronous discharge, suggestive of Creutzfeldt-Jakob disease. However, a brain biopsy revealed infiltration of atypical lymphoid cells expressing CD20, and the anti-NH2 terminal of the α-enolase antibody was detected, diagnosing the complication with lymphomatosis cerebri and HE. High-dose intravenous methylprednisolone therapy and oral prednisolone with whole cranial irradiation enabled her to have simple conversations and consume food orally; however, severe cognitive impairment persisted. Although HE is a rare complication of malignant lymphoma, clinicians should be aware that it could be strongly suspected if the clinical symptoms worsen in the absence of imaging changes.

Electrolyzed Hydrogen Water Protects against Ethanol-Induced Cytotoxicity by Regulating Aldehyde Metabolism-Associated Enzymes in the Hepatic Cell Line HepG2.

Excessive alcohol consumption can cause multi-systemic diseases. Among them, alcoholic liver disease is the most frequent and serious disease. Electrolytic hydrogen water (EHW) is produced at the cathode during electrolysis of water and contains a large amount of molecular hydrogen and a low content of platinum nanoparticles with alkaline properties. In this study, we found that EHW inhibits ethanol-induced cytotoxicity by decreasing the intracellular acetaldehyde, a toxic substance produced by ethanol degradation, in hepatocyte cell lines HepG2. Analysis of the mechanism of action revealed that EHW inhibits the metabolism of ethanol to acetaldehyde by suppressing alcohol dehydrogenase. EHW also promotes the metabolism of acetaldehyde to acetic acid by activating aldehyde dehydrogenase, which plays to reduce aldehyde toxicity and intracellular reactive oxygen species in HepG2 cells. These functions were correlated with the concentration of molecular hydrogen in EHW, and were abolished by degassing treatment, suggesting that molecular hydrogen may contribute as a functional factor in the suppression of ethanol-induced hepatocellular damage. Furthermore, hydrogen water with high dissolved hydrogen molecule showed the same hepatocellular protective effect against ethanol as the EHW. These results suggest that EHW may be useful in the prevention of alcoholic liver disease.

Serum BDNF as a Potential Biomarker of Alzheimer's Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy.

There is an urgent need to establish blood biomarkers for Alzheimer's disease (AD). Although it has been speculated that brain-derived neurotrophic factor (BDNF) is associated with AD, whether it can be used as a blood biomarker has yet to be determined. We used serum, cerebrospinal fluid (CSF), and medial temporal lobe atrophy from patients with AD to evaluate the association of BDNF with AD and assess its severity. For the blood analysis, 66 participants [21 normal controls (NCs) with normal cognitive function, 22 patients with mild cognitive impairment (MCI) due to AD, and 23 patients with AD] were included. For the CSF analysis, 30 participants were included. Magnetic resonance imaging, including a voxel-based specific regional analysis system for AD, and a Mini Mental State Examination were performed. Serum levels of BDNF and CSF levels of amyloid-ß42, total tau, and phosphorylated tau were measured using ELISA. Serum BDNF levels were significantly lower in the MCI due to AD group than in the NC group (p = 0.037). Although there was no significant difference in the AD group, there was a downward trend compared to the NC group. Serum BDNF levels were positively correlated with CSF Aß42 levels (r = 0.49, p = 0.005). There was a significant correlation between serum BDNF levels and medial temporal lobe atrophy. Decreased serum BDNF can potentially be used as a biomarker for early AD detection. Early detection of AD with a less invasive blood test is very beneficial, as it allows for intervention before dementia progresses.

Sex Differences in the Relationship of Serum Vitamin B1 and B12 to Dementia Among Memory Clinic Outpatients in Japan.

Dementia and cognitive impairment are considered to be one of the biggest social and medical problems. While there is a definite relationship between vitamin B and cognitive decline, this has yet to be fully assessed with regard to sex differences. Thus, the present study investigated the relationship of vitamin B1 or vitamin B12 with dementia in accordance with the sex in 188 patients who visited the Memory Clinic at Showa University Hospital in Japan from March 2016 to March 2019. Cognitive function was tested by the Japanese version of the Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-Revised (HDS-R). Blood tests were performed to measure the vitamin levels. Logistic regression analysis was used to calculate the odds ratio (OR) for dementia and the 95% confidence interval (CI). Compared to the highest vitamin group (third tertile), the lowest vitamin group (first tertile) exhibited a significantly increased OR for dementia defined by MMSE for vitamin B1 (OR:3.73, 95% CI:1.52-9.16) and vitamin B12 (2.97, 1.22-7.28) among women. In contrast, vitamin levels were not significantly associated with dementia determined by MMSE in men. These findings were similar even when dementia was defined by HDS-R. The present study suggests that vitamin B1 plays a role in preventing development of dementia in women. Future longitudinal studies will need to be undertaken in order to examine whether decreasing vitamin levels occur before or after cognitive impairment, and whether maintaining a higher vitamin level can prevent a worsening of cognitive function and the development of dementia.

Toxic Amyloid-ß42 Conformer May Accelerate the Onset of Alzheimer's Disease in the Preclinical Stage.

BACKGROUND: Toxic amyloid-ß protein (Aß) conformers play an important role in the progression of Alzheimer's disease (AD). The ratio of toxic conformer to total Aß42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. OBJECTIVE: We compared the toxic Aß42, conformer at different stages of AD to identify its contribution to AD pathogenesis. METHODS: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aß42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aß conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). RESULTS: Toxic Aß conformer level was insignificant between groups, but its ratio to Aß42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aß42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = -0.38, p < 0.05). CONCLUSION: Toxic Aß conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

Cingulate Island Sign in Single Photon Emission Computed Tomography: Clinical Biomarker Correlations in Lewy Body Disease and Alzheimer's Disease.

We compared 'CIScore' determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer's disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Identification of Dietary Phytochemicals Capable of Enhancing the Autophagy Flux in HeLa and Caco-2 Human Cell Lines.

Autophagy is a major degradation system for intracellular macromolecules. Its decline with age or obesity is related to the onset and development of various intractable diseases. Although dietary phytochemicals are expected to enhance autophagy for preventive medicine, few studies have addressed their effects on the autophagy flux, which is the focus of the current study. Herein, 67 dietary phytochemicals were screened using a green fluorescent protein (GFP)-microtubule-associated protein light chain 3 (LC3)-red fluorescent protein (RFP)-LC3ΔG probe for the quantitative assessment of autophagic degradation. Among them, isorhamnetin, chrysoeriol, 2,2',4'-trihydroxychalcone, and zerumbone enhanced the autophagy flux in HeLa cells. Meanwhile, analysis of the structure-activity relationships indicated that the 3'-methoxy-4'-hydroxy group on the B-ring in the flavone skeleton and an ortho-phenolic group on the chalcone B-ring were crucial for phytochemicals activities. These active compounds were also effective in colon carcinoma Caco-2 cells, and some of them increased the expression of p62 protein, a typical substrate of autophagic proteolysis, indicating that phytochemicals impact p62 levels in autophagy-dependent and/or -independent manners. In addition, these compounds were characterized by distinct modes of action. While isorhamnetin and chrysoeriol enhanced autophagy in an mTOR signaling-dependent manner, the actions of 2,2',4'-trihydroxychalcone and zerumbone were independent of mTOR signaling. Hence, these dietary phytochemicals may prove effective as potential preventive or therapeutic strategies for lifestyle-related diseases.

Increased Presence of Cerebral Microbleeds Correlates With Ventricular Enlargement and Increased White Matter Hyperintensities in Alzheimer's Disease.

Objective: To investigate whether the number of cerebral microbleeds (CMB) could be a useful indicator to predict glymphatic system dysfunction in Alzheimer's disease (AD) patients, by comparing the degree of cerebral spinal fluid (CSF) and interstitial fluid (ISF) stasis. Methods: Forty probable AD patients were included, with those exhibiting two or more CMB were included in the multiple CMB group (mCMB, n = 21, mean = 11.1), and none or one CMB included in the non-multiple CMB group (nmCMB, n = 19, mean = 0.84). CMB was defined in axial gradient recalled echo (GRE) T2*-weighted images. Evans index (EI) was calculated to measure lateral ventricle enlargement, Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) software was used to determine the extent of gray and white matter atrophy, and Fazekas scale (FS) was used to determine white matter hyperintensities (WMH). Results: EI was significantly larger in mCMB than in nmCMB, while the gray and white matter volume was not different between groups. Thus, the difference in lateral ventricle enlargement between AD with and without multiple CMB reflects a combination of the degree of brain atrophy and the extent of CSF stasis. FS was higher in mCMB than in the nmCMB, suggesting the failure of ISF elimination was more severe in mCMB cases. Conclusion: The difference in lateral ventricle enlargement and WMH between AD with or without multiple CMB may reflect a difference in the degree of CSF/ISF stagnation.

Correlated levels of cerebrospinal fluid pathogenic proteins in drug-naïve Parkinson's disease.

BACKGROUND AND AIM: Toxic oligomeric α-synuclein (αS; O-αS) has been suggested to play a central role in the pathogenesis of Lewy body diseases such as Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of αS, O-αS, total and phosphorylated tau, and amyloid ß 1-42 (Aß1-42) are thought to reflect the pathophysiology or clinical symptoms in PD. In this study, we examined correlations of the CSF levels of these proteins with the clinical symptoms, and with each other in drug-naïve patients with PD. METHODS: Twenty-seven drug-naïve patients with PD were included. Motor and cognitive functions were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), and Neurobehavioral Cognitive Status Examination (COGNISTAT). CSF levels of total αS, O-αS, Aß1-42, total tau and tau phosphorylated at threonine 181 (P-tau181p) were measured. CSF levels of these proteins were compared with clinical assessments from the UPDRS, MoCA and COGNISTAT using Spearman correlation analysis. Spearman correlation coefficients among CSF protein levels were also evaluated. RESULTS: CSF levels of αS were negatively correlated with UPDRS part III (motor score) (p < 0.05) and bradykinesia (p < 0.01), and positively correlated with COGNISTAT subtest of judgement (p < 0.01) and CSF levels of Aß1-42 (p < 0.001), total tau (p < 0.001) and P-tau181p (p < 0.01). Lower CSF levels of Aß1-42, total tau and P-tau181p were significantly related to worsening of some motor and/or cognitive functions. The CSF level of O-αS showed no correlation with any motor and cognitive assessments or with CSF levels of the other proteins. CONCLUSION: CSF levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins in drug-naïve PD patients. These correlations suggest a central role for interaction and aggregation of αS with Aß1-42, tau, and phosphorylated tau in the pathogenesis of PD. Although O-αS has been shown to have neurotoxic effects, CSF levels do not reflect clinical symptoms or levels of other proteins in cross-sectional assessment.

High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid ß-protein (Aß) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aß species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aß1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aß1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aß1-42 were significantly greater than those of LMW-Aß1-42. Therapeutic reduction of HMW-Aß1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

The relationship between thyroid function and cerebral blood flow in mild cognitive impairment and Alzheimer's disease.

The thyroid hormones have been reported to be associated with cognitive decline and Alzheimer's disease. The relationship between thyroid function within the normal range and cerebral blood flow in Alzheimer's disease patients has been shown in a recent study. Mild cognitive impairment is often the first stage of Alzheimer's disease; thus, early diagnosis is important. The present study investigated the relationship between thyroid function and regional cerebral blood flow in patients with mild cognitive impairment and Alzheimer's disease. A total of 122 memory clinic outpatients who underwent thyroid function testing and single photon emission computed tomography were divided into mild cognitive impairment, Alzheimer's disease, and Normal groups. Regional cerebral blood flow was calculated using a three-dimensional stereotactic region of interest template in an automated cerebral perfusion single photon emission computed tomography analysis system. Multiple regression analysis adjusted for age and sex was conducted to examine the relationships between thyroid hormones and regional cerebral blood flow. Thyroid stimulating hormone was significantly associated with regional cerebral blood flow in the bilateral temporal, bilateral pericallosal, and bilateral hippocampal regions in the mild cognitive impairment group. In the Alzheimer's disease group, free triiodothyronine was significantly associated with regional cerebral blood flow in the bilateral parietal, right temporal, and bilateral pericallosal regions. The present study showed the association of thyroid stimulating hormone with regional cerebral blood flow in the mild cognitive impairment group and the association of free triiodothyronine with regional cerebral blood flow in the Alzheimer's disease group. These study findings could contribute to the early diagnosis of mild cognitive impairment at general memory clinics and the prevention of subsequent progression to Alzheimer's disease.

High serum high-density lipoprotein-cholesterol is associated with memory function and gyrification of insular and frontal opercular cortex in an elderly memory-clinic population.

The issue of whether serum lipid marker values are cognitively and neurologically significant for elderly individuals attending a memory clinic has been controversial. We investigated the associations of serum lipid markers with the memory function and cortical structure in 52 patients aged ≥75 years who had attended our memory clinic based on their subjective memory complaints. None had a history of medication for hyperlipidemia. The Wechsler Memory Scale-Revised (WMS-R) was administered to all patients for the assessment of their memory function. Serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDLC), and triglyceride (TG) were measured for each patient. Surface-based morphometry (SBM) was performed for the calculation of each patient's cortical thickness and gyrification index based on structural MRI data. Our analyses revealed that the serum HDLC level was positively and significantly correlated with the WMS-R subtests of visual paired associates I/II and logical memory I (p < 0.05). The serum TG level was negatively correlated with the logical memory I subtest. The SBM results showed positive correlations between the serum HDLC level and the gyrification indices of the bilateral insular and frontal opercular cortices, and those two gyrification indices were positively correlated with the logical memory I and visual paired associates I/II. These results suggest that in these elderly patients, a high serum HDLC level was associated with not only preserved memory function but also gyrification of the insular and frontal opercular cortex. We conclude that elderly individuals' serum lipid markers should be carefully assessed in memory clinic settings, because serum HDLC may be a biomarker for memory function and cortical structure.

Involvement of ERK1/2-mediated ELK1/CHOP/DR5 pathway in 6-(methylsulfinyl)hexyl isothiocyanate-induced apoptosis of colorectal cancer cells.

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabi. Although 6-MSITC is reported to have cancer chemopreventive activities in rat model, the molecular mechanism is unclear. In this study, we investigated the anticancer mechanisms using two types of human colorectal cancer cells (HCT116 p53+/+ and p53-/-). 6-MSITC caused cell cycle arrest in G2/M phase and induced apoptosis in both types of cells in the same fashion. Signaling data revealed that the activation of ERK1/2, rather than p53, is recruited for 6-MSITC-induced apoptosis. 6-MSITC stimulated ERK1/2 phosphorylation, and then activated ERK1/2 signaling including ELK1 phosphorylation, and upregulation of C/EBP homologous protein (CHOP) and death receptor 5 (DR5). The MEK1/2 inhibitor U0126 blocked all of these molecular events induced by 6-MSITC, and enhanced the cell viability in both types of cells in the same manner. These results indicated that ERK1/2-mediated ELK1/CHOP/DR5 pathway is involved in 6-MSITC-induced apoptosis in colorectal cancer cells. Abbreviations: CHOP: C/EBP homologous protein; DR5: death receptor 5; ELK1: ETS transcription factor; ERK1/2: extracellular signal-regulated kinase 1/2; JNK: Jun-N-terminal kinase; MAPK: mitogen-activated protein kinase; MEK1/2: MAP/ERK kinase 1/2; 6-MSITC: 6-(methylsulfinyl)hexyl isothiocyanate; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP: poly(ADP-ribose) polymerase.