White matter hyperintensities in cholinergic pathways are associated with dementia severity in e4 carriers but not in non-carriers.

Background and objectives: Among individuals with Alzheimer's disease (AD), APOE e4 carriers with increased white matter hyperintensities (WMHs) may selectively be at increased risk of cognitive impairment. Given that the cholinergic system plays a crucial role in cognitive impairment, this study aimed to identify how APOE status modulates the associations between dementia severity and white matter hyperintensities in cholinergic pathways. Methods: From 2018 to 2022, we recruited participants (APOE e4 carriers, n = 49; non-carriers, n = 117) from the memory clinic of Cardinal Tien Hospital, Taipei, Taiwan. Participants underwent brain MRI, neuropsychological testing, and APOE genotyping. In this study, we applied the visual rating scale of the Cholinergic Pathways Hyperintensities Scale (CHIPS) to evaluate WMHs in cholinergic pathways compared with the Fazekas scale. Multiple regression was used to assess the influence of CHIPS score and APOE carrier status on dementia severity based on Clinical Dementia Rating-Sum of Boxes (CDR-SB). Results: After adjusting for age, education and sex, higher CHIPS scores tended to be associated with higher CDR-SB in APOE e4 carriers but not in the non-carrier group. Conclusions: Carriers and non-carriers present distinct associations between dementia severity and WMHs in cholinergic pathways. In APOE e4 carriers, increased white matter in cholinergic pathways are associated with greater dementia severity. In non-carriers, WMHs exhibit less predictive roles for clinical dementia severity. WMHs on the cholinergic pathway may have a different impact on APOE e4 carriers vs. non-carriers.

White matter hyperintensities in cholinergic pathways may predict poorer responsiveness to acetylcholinesterase inhibitor treatment for Alzheimer's disease.

BACKGROUND: Acetylcholinesterase inhibitor (AChEI) drug regimens are the mainstay treatment options for patients with Alzheimer's disease (AD). Herein, We examined the association between clinical response to AChEI and white matter hyperintensities on magnetic resonance imaging (MRI) scan at baseline. METHODS: Between 2020 and 2021, we recruited 101 individuals with a clinical diagnosis of probable AD. Each participant underwent complete neuropsychological testing and 3T (Telsa) brain magnetic resonance imaging. Responsiveness to AChEI, as assessed after 12 months, was designated as less than two points of regression in Mini-Mental State Examination scores (MMSE) and stable clinical dementia rating scale. We also evaluated MRI images by examining scores on the Cholinergic Pathways Hyperintensities Scale (CHIPS), Fazekas scale, and medial temporal atrophy (MTA) scale. RESULTS: In our cohort, 52 patients (51.4%) were classified as responders. We observed significantly higher CHIPS scores in the nonresponder group (21.1 ± 12.9 vs. 14.9 ± 9.2, P = 0.007). Age at baseline, education level, sex, Clinical Dementia Rating sum of boxes scores, and three neuroimaging parameters were tested in regression models. Only CHIPS scores predicted clinical response to AChEI treatment. CONCLUSION: WMHs in the cholinergic pathways, not diffuse white matter lesions or hippocampal atrophy, correlated with poorer responsiveness to AChEI treatment. Therefore, further investigation into the role of the cholinergic pathway in AD is warranted.

Predictability effect on N400 reflects the severity of reading comprehension deficits in aphasia.

Predictability effect on N400, in which low predictability words elicited a larger N400 than high predictability words did over central to posterior electrodes, has been used to index difficulty of lexical retrieval and semantic integration of words in sentence comprehension. This study examined predictability effect on N400 in aphasic patients to determine if the properties of N400 are suited to indexing the severity of reading comprehension deficits. Patients with aphasia were divided into high and low ability groups based on scores on the reading comprehension subtest in the Chinese Concise Aphasia Test (CCAT). The two aphasia groups, a group of healthy elders who were age-matched to the aphasic participants, and a group of young adults, were requested to read sentences that either ended with highly predictable words or unexpected but plausible words, while undergoing electroencephalography (EEG). The young adult and healthy elderly groups exhibited the typical centro-parietal distributed effect of predictability on N400; however, healthy elders exhibited a reduced N400 effect in a delayed time window compared to the young adults. Compared with the elderly control, the high ability aphasia group exhibited a comparable N400 effect in a more restricted time window; by contrast, the low ability aphasia group exhibited a frontal distributed N400 in a much later time window (400-700 ms). These data suggest that the severity of reading comprehension deficits affects predictability effect on a set of N400 characteristics (i.e., amplitude, time window, and topographic distribution), which may be effective as ERP signatures in the evaluation of language recovery in aphasia.

Demethoxycurcumin, a major active curcuminoid from Curcuma longa, suppresses balloon injury induced vascular smooth muscle cell migration and neointima formation: an in vitro and in vivo study.

SCOPE: Curcumin has been shown to affect platelet-derived growth factor (PDGF)- and tumor necrosis factor (TNF)-α-elicited vascular smooth muscle cell (VSMC) migration and inhibit neointima formation following vascular injury. However, whether two other curcuminoids isolated from Curcuma longa, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), also demonstrate antimigratory activity in VSMCs similar to that of curcumin remain uncharacterized. METHODS AND RESULTS: Based on 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and proliferating cell nuclear antigen immunostaining analyses as well as changes in intima/media ratios, we show that DMC exhibits more potent effects than the other curcuminoids. We aimed to evaluate the effects and characterize the molecular mechanisms of DMC on VSMC migration and neointima formation in a carotid injury model. DMC decreased the expression of matrix metalloproteinase 2/9 and inhibited VSMC migration as demonstrated by in vitro scratch wound and transwell assays. Furthermore, DMC may inhibit the migration of VSMCs by reducing the expression of matrix metalloproteinase 2/9 via downregulation of the focal adhesion kinase/phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B) and phosphoglycerate kinase 1/extracellular signal regulated kinase 1/2 signaling pathways. Using a rat carotid arterial injury model, we show that DMC treatment was more potent than treatment with the other curcuminoids with respect to reducing intima/media ratios and the number of proliferating cells. CONCLUSION: DMC should be considered for therapeutic use in preventing VSMC migration and attenuating restenosis following balloon-mediated vascular injury.

Number of sense effects of Chinese disyllabic compounds in the two hemispheres.

The current study manipulated the visual field and the number of senses of the first character in Chinese disyllabic compounds to investigate how the related senses (polysemy) of the constituted character in the compounds were represented and processed in the two hemispheres. The ERP results in experiment 1 revealed crossover patterns in the left hemisphere (LH) and the right hemisphere (RH). The sense facilitation in the LH was in favor of the assumption of single-entry representation for senses. However, the patterns in the RH yielded two possible interpretations: (1) the nature of hemispheric processing in dealing with sublexical sense ambiguity; (2) the semantic activation from the separate-entry representation for senses. To clarify these possibilities, experiment 2 was designed to push participants to a deeper level of lexical processing by the word class judgment. The results revealed the sense facilitation effect in the RH. In sum, the current study was in support of the single-entry account for related senses and demonstrated that two hemispheres processed sublexical sense ambiguity in a complementary way.