On Psychological Continuity and Dementia

This letter responds to the article “On the Authority of Advance Euthanasia Directives for People with Severe Dementia: Reflections on a Dutch Case,” by Henri Wijsbek and Thomas Nys, in the September-October 2022 issue of the Hastings Center Report.     

The Risk of Alzheimer's Disease After Acute Appendicitis With or Without Appendectomy

ObjectivePrevious epidemiologic studies have suggested an association between appendectomy and Parkinson's disease. The aim of the current study was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis.DesignPopulation-based cohort study.Setting and participantsWe used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years. Cases and controls underwent 1:1 matching by age, sex, index date, and dementia-related comorbidities.MethodsThe primary outcome was AD, and secondary outcomes included other dementia types. Adjusted hazard ratios (aHRs) were calculated, and a competing risk regression model was created. The E value for causality of evidence was calculated.ResultsPatients developing appendicitis (0.6% vs 0.1%, P = .005) and those receiving appendectomy for appendicitis (0.4% vs 0.1%, P = .003) had higher incidences of AD than the controls during the follow-up period. A Cox regression analysis with adjustment for potential confounders showed that patients with appendicitis [aHR 6.68, 95% confidence interval (CI) 1.84-24.48] and those receiving appendectomy for appendicitis (aHR 5.01, 95% CI 1.33-18.85) were more likely to develop AD than the controls. These 2 groups also had higher risks for unspecified dementia and all types of dementia but not for vascular dementia than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis. The competing risk regression models and the E values support the study findings.Conclusions and implicationsAfter recovery from appendicitis, these patients should be followed up for signs of AD.     

补肾活血方对血管性痴呆大鼠海马神经细胞自噬的影响＊

目的 探究补肾活血方对血管性痴呆（Vascular Dementia， VD）大鼠模型自噬的影响。方法 52周龄SD雄性大鼠50只，随机分为假手术组（Sham组）、模型组（VD组）、模型+补肾活血方组（BSHX组）、模型+雷帕霉素组（Rap组）和模型+3-甲基腺嘌呤组（3-MA组），每组10只大鼠。除Sham组外其余各组采用两血管阻断法（2-VO）建立VD模型。BSHX组中药灌胃治疗28天；自噬干预组于造模前30 min侧脑室给药。运用Morris水迷宫测试各组大鼠的学习记忆能力；通过尼氏染色和透射电子显微镜（Transmission electron microscope，TEM）观察大鼠海马区病理形态及自噬变化；采用蛋白免疫印迹（Western blot）法和反转录实时荧光定量PCR（RT-qPCR）检测大鼠海马Beclin-1、P62以及微管相关蛋白1轻链3（LC3）蛋白及mRNA表达情况。结果 与VD组比较，BSHX组大鼠学习记忆能力显著提升（P<0.05），镜下观察BSHX组和3-MA组的细胞形态及数量均有改善，自噬小体鲜见，Beclin-1以及LC3蛋白和mRNA表达水平显著降低（P<0.05），P62蛋白和mRNA表达水平明显升高（P<0.05）结论 补肾活血方可以降低VD大鼠海马区Beclin-1和LC3蛋白及mRNA的表达，提高P62的表达，通过抑制自噬的发生，减轻对神经细胞的损伤，改善学习记忆能力。     

Interoception Primes Emotional Processing: Multimodal Evidence from Neurodegeneration

Recent frameworks in cognitive neuroscience and behavioral neurology underscore interoceptive priors as core modulators of negative emotions. However, the field lacks experimental designs manipulating the priming of emotions via interoception and exploring their multimodal signatures in neurodegenerative models. Here, we designed a novel task that involves interoceptive and control-exteroceptive priming conditions followed by post-interoception and post-exteroception facial emotion recognition (FER). We recruited 114 participants, including healthy controls (HCs) as well as patients with behavioral variant frontotemporal dementia (bvFTD), Parkinson''s disease (PD), and Alzheimer''s disease (AD). We measured online EEG modulations of the heart-evoked potential (HEP), and associations with both brain structural and resting-state functional connectivity patterns. Behaviorally, post-interoception negative FER was enhanced in HCs but selectively disrupted in bvFTD and PD, with AD presenting generalized disruptions across emotion types. Only bvFTD presented impaired interoceptive accuracy. Increased HEP modulations during post-interoception negative FER was observed in HCs and AD, but not in bvFTD or PD patients. Across all groups, post-interoception negative FER correlated with the volume of the insula and the ACC. Also, negative FER was associated with functional connectivity along the (a) salience network in the post-interoception condition, and along the (b) executive network in the post-exteroception condition. These patterns were selectively disrupted in bvFTD (a) and PD (b), respectively. Our approach underscores the multidimensional impact of interoception on emotion, while revealing a specific pathophysiological marker of bvFTD. These findings inform a promising theoretical and clinical agenda in the fields of nteroception, emotion, allostasis, and neurodegeneration.SIGNIFICANCE STATEMENT We examined whether and how emotions are primed by interoceptive states combining multimodal measures in healthy controls and neurodegenerative models. In controls, negative emotion recognition and ongoing HEP modulations were increased after interoception. These patterns were selectively disrupted in patients with atrophy across key interoceptive-emotional regions (e.g., the insula and the cingulate in frontotemporal dementia, frontostriatal networks in Parkinson''s disease), whereas persons with Alzheimer''s disease presented generalized emotional processing abnormalities with preserved interoceptive mechanisms. The integration of both domains was associated with the volume and connectivity (salience network) of canonical interoceptive-emotional hubs, critically involving the insula and the anterior cingulate. Our study reveals multimodal markers of interoceptive-emotional priming, laying the groundwork for new agendas in cognitive neuroscience and behavioral neurology.     

香萱益神方对血管性痴呆模型大鼠神经元凋亡机制研究

目的:探讨香萱益神方治疗血管性痴呆(VD)模型大鼠认知功能作用及其对神经元凋亡机制的研究。方法:两血管阻断法建立VD大鼠模型,给予中药方香萱益神方灌胃治疗6周,分别于造模后、中药喂养6周后进行Morris水迷宫行为学检测,测试大鼠认知行为能力改变,行为学测试结束后,检测VD模型大鼠海马中海马组织脑源性神经营养因子(BDNF)表达水平的变化。结果:香萱益神方治疗6周后,血管性痴呆大鼠模型学习记忆能力得到改善,上调脑内海马组织神经营养因子水平,海马神经元凋亡率下降。结论:香萱益神方是治疗血管性痴呆的有效方剂,可以有效改善VD大鼠模型认知行为功能的障碍情况,起到减少海马神经元细胞凋亡,诱导海马神经元细胞修复的作用。香萱益神方可能是通过激活BDNF相关通路,起到保护海马神经元的作用。     

A review of dementia,focusing on the distinct roles of viral protein corona and MMP9 in dementia: Potential pharmacotherapeutic priorities

Dementia, in particular, is a defining feature of Alzheimer's and Parkinson's diseases. Because of the combination of motor and cognitive impairments, Parkinson's disease dementia (PDD) has a greater impact on affected people than Alzheimer's disease dementia (ADD) and others. If one family member develops dementia, the other members will suffer greatly in terms of social and occupational functioning. Currently, no relevant treatment is available based on an examination of the absolute pathophysiology of dementia. As a result, our objective of current review encouraged to look for dementia pharmacotherapy based on their pathogenesis. We systematically searched electronic databases such as PubMed, Scopus, and ESCI for information on the pathophysiology of demetia, as well as their treatment with allopathic and herbal medications. By modulating intermediate proteins, oxidative stress, viral protein corona, and MMP9 are etiological factors that cause dementia. The pathophysiology of ADD was described by two hypotheses: the amyloid cascade hypothesis and the tau and tangle hypothesis. ADD is caused by an increase in amyloid-beta (Aβ) and neurofibrillary tangles in the cerebrum. The viral protein corona (VPC) is more contagious and helps to form amyloid-beta (Aβ) plaques and neurofibrillary tangles in the cerebrum. Thioredoxin interacting protein (TXNIP) inside the BBB encourages Aβ to become more engaged. PDD is caused by decreased or absent dopamine secretion from nerve cells in the substantia nigra, as well as PRKN gene deletion/duplication mutations, and shift in the PRKN-PACRG organisation, all of which are linked to ageing. This article discussed the pathophysiology of dementia, as well as a list of herbal medications that can easily cross the BBB and have a therapeutic effect on dementia.     

生慧汤对APP/PS1雄性AD小鼠海马内APP代谢产物的昼夜变化影响＊

目的研究生慧汤对APP/PS1（β-amyloid precursor protein/presenilin 1246E）小鼠海马内β淀粉样前体蛋白（Amyloid precursor protein，APP）代谢产物昼夜表达的影响。方法 将56只雄性APP/PS1双转基因痴呆模型小鼠随机分为4组，分别为：痴呆模型组、褪黑素治疗组（0.78 mg·kg^-1·d^-1）、生慧汤高剂量组（27.0 g·kg^-1·d^-1）、生慧汤低剂量组（13.5 g·kg^-1·d^-1），每组14只；对照组为14只雄性C57BL/6J小鼠，连续给药30天。采用Morris水迷宫检测小鼠学习记忆能力，采用酶联免疫吸附检测（ELISA）检测不同时间段取出的海马组织sAPPα含量。对海马β淀粉样蛋白_1-40、β淀粉样蛋白_1-42表达进行免疫印迹分析。免疫组化（IHC）检测海马CA1区Aβ_1-40蛋白的表达。结果 Morris水迷宫结果表明，与对照组相比，模型组上平台潜伏期明显延长、穿越平台次数明显减少（P<0.01）；与模型组相比，生慧汤不同剂量组上平台潜伏期明显缩短（P<0.01、P<0.05），穿越平台次数明显增加（P<0.05）。ELISA结果表明，与对照组相比，模型组的sAPPα总量、各时间段（12：00、24：00）sAPPα含量明显减少（P<0.01）；与模型组相比，生慧汤不同剂量组sAPPα总量明显增多（P<0.01、P<0.05），生慧汤高剂量组仅能增加12：00 sAPPα含量（P<0.01），生慧汤低剂量组仅能增加24：00 sAPPα含量（P<0.05）。对照组sAPPα含量具有明显昼夜差异（P<0.01）。模型组sAPPα含量的昼夜差异性消失（P>0.05）。生慧汤高剂量组sAPPα含量具有昼夜差异（P<0.01），生慧汤低剂量组sAPPα含量不具有昼夜差异（P>0.05）。Western blot结果显示，与对照组相比，模型组Aβ_1-40、Aβ_1-42蛋白表达明显增加（P<0.01）；与模型组相比，生慧汤高剂量组Aβ_1-40、Aβ_1-42蛋白表达减少（P<0.05、P<0.01）；生慧汤低剂量组仅能减少Aβ_1-40蛋白的表达（P<0.05），对Aβ_1-42蛋白表达无影响（P>0.05）。免疫组化结果表明，与对照组相比，模型组Aβ_1-40表达明显增加（P<0.01）；与模型组相比，生慧汤不同剂量组Aβ_1-40表达不同程度减少（P<0.01、P<0.05）。结论 生慧汤能够改善5月龄APP/PS1阿尔茨海默病模型小鼠的学习记忆障碍，其机制可能与恢复海马内APP代谢产物sAPPα的昼夜节律性表达、从而减少Aβ的沉积有关。     

Implementation of Nurse-Led Cognitive Screening During Medicare Annual Wellness Visits

Dementia is a serious and costly illness. Early identification of cognitive impairment provides opportunity for earlier intervention, and there is growing evidence suggesting that early intervention may help delay the onset of dementia. There is limited concensus and standardized recommendations for when and how cognitive screening should occur. This quality improvement project implemented a standardized nurse-led cognitive screening workflow during the Medicare annual wellness visit. Statistically significant differences were found between the baseline and implementation groups for Mini-Cog screening rates and referral for follow-up for further neurocognitive evaluation. A structured nurse-led workflow improved the cognitive screening process, providing opportunity for further evaluation and intervention.