Building of a Clinical Prediction Model for Hemodynamic Depression after Carotid Artery Stenting / 中国医学科学院学报

Objective To analyze the risk factors and build a clinical prediction model for hemodynamic depression (HD) after carotid artery stenting (CAS). Methods A total of 116 patients who received CAS in the Department of Vascular Surgery,Drum Tower Clinical College of Nanjing Medical University and the Department of Vascular Surgery,the Affiliated Suqian First People's Hospital of Nanjing Medical University from January 1,2016 to January 1,2022 were included in this study.The patients were assigned into a HD group and a non-HD group.The clinical baseline data and vascular disease characteristics of each group were collected,and multivariate Logistic regression was employed to identify the independent predictors of HD after CAS and build a clinical prediction model.The receiver operating characteristic (ROC) curve was drawn,and the area under the ROC curve (AUC) was calculated to evaluate the predictive performance of the model. Results The HD group had lower proportions of diabetes (P=0.014) and smoking (P=0.037) and higher proportions of hypertension (P=0.031),bilateral CAS (P=0.018),calcified plaque (P=0.001),eccentric plaque (P=0.003),and the distance<1 cm from the minimum lumen level to the carotid bifurcation (P=0.009) than the non-HD group.The age,sex,coronary heart disease,symptomatic carotid artery stenosis,degree of stenosis,and length of lesions had no statistically significant differences between the HD group and the non-HD group (all P>0.05).Based on the above predictive factors,a clinical prediction model was established,which showed the AUC of 0.807 and the 95% CI of 0.730-0.885 (P<0.001).The model demonstrated the sensitivity of 62.7% and the specificity of 87.7% when the best cut-off value of the model score reached 12.5 points. Conclusions Diabetes,smoking,calcified plaque,eccentric plaque,and the distance<1 cm from the minimum lumen level to the carotid bifurcation are independent predictors of HD after CAS.The clinical prediction model built based on the above factors has good performance in predicting the occurrence of HD after CAS.

β-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition.

Cardiac magnetic resonance and amyloidosis: review / Ressonância magnética cardíaca e amiloidose: revisão

Amyloidosis is a disease caused by extracellular deposition of insoluble protein fibrils, that results in changes in tissue architecture and consequently modification of the organ structure. Cardiac involvement is common in amyloidosis. Two major types of systemic amyloidosis affect the myocardium ­ immunoglobulin light chain and transthyretin amyloidosis ­ each leading to different prognosis. Early detection and diagnosis of cardiac amyloidosis are the main objectives in the assessment of the disease. New techniques of magnetic resonance imaging have minimized the need for biopsies for the diagnosis. Late gadolinium enhancement technique, and more recently T1 mapping, have allowed a simplified evaluation of amyloid deposits and extracellular volume. The aim of this review was to describe basic concepts and updates of the use of magnetic resonance imaging for the diagnosis amyloidosis and evaluation of its severity

Prediction of Alzheimer's Pathological Changes in Subjective Cognitive Decline Using the Self-report Questionnaire and Neuroimaging Biomarkers

BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may be the first symptomatic stage of Alzheimer's disease (AD). Hence, a screening tool to characterize the patients' complaints and assess the risk of AD is required. We investigated the SCD neuroimaging biomarker distributions and the relevance between the self-report questionnaire and Alzheimer's pathologic changes. METHODS: Individuals aged 50 and above with consistent cognitive complaints without any objective cognitive impairments were eligible for the study. The newly developed questionnaire consisted of 2 parts; 10 questions translated from the ‘SCD-plus criteria’ and a Korean version of the cognitive failure questionnaire by Broadbent. All the subjects underwent physical examinations such as blood work, detailed neuropsychological tests, the self-report questionnaire, brain magnetic resonance imagings, and florbetaben positron emission tomography (PET) scans. Amyloid PET findings were interpreted using both visual rating and quantitative analysis. Group comparisons and association analysis were performed using SPSS (version 18.0). RESULTS: A total of 31 participants with SCD completed the study and 25.8% showed positive amyloid depositions. The degree of periventricular white matter hyperintensities (WMH) and hippocampal atrophy were more severe in amyloid-positive SCDs compared to the amyloid-negative group. In the self-reported questionnaire, the ‘informant's report a decline’ and ‘symptom's onset after 65 years of age’ were associated with more Alzheimer's pathologic changes. CONCLUSIONS: Amyloid-positive SCDs differed from amyloid-negative SCDs on WMH, hippocampal atrophy, and a few self-reported clinical features, which gave clues on the prediction of AD pathology.

Effect of Amyloid Deposition in PET on Hippocampal Metabolism in Amnestic-Mild Cognitive Impairment : Pilot Study / 생물치료정신의학

OBJECTIVES: Most studies of hippocampal metabolism(HM) in amnestic mild cognitive impairment(aMCI) gave inconsistent results. Our objective was to evaluate the effect of amyloid-beta(Aβ) status on hippocampal metabolism in aMCI.METHODS: Overall, 23 aMCI underwent three-dimensional magnetic resonance imaging(MRI), ¹⁸F-fluorodeoxyglucose-positron emission tomography(¹⁸FDG-PET) and ¹⁸F-Fluorbetaben amyloid positron emission tomography (amyloid-PET). According to Aβ status on amyloid PET, 23 aMCI were classified as either Aβ+aMCI(N=13) or Aβ−aMCI(N=10). The primary outcome was HM using ¹⁸FDG-PET and we investigate the difference on HM between Aβ+aMCI and Aβ−aMCI using analysis of variance(ANOVA) model, after controlling hippocampal volume.RESULTS: We found that HM was more decreased in Aβ+aMCI than Aβ−aMCI. This result was not changed after controlling hippocampal volume.CONCLUSION: Our findings suggest that Aβ+ is associated with decreased HM, regardless of hippocampal volume, in aMCI.

The Effect of Clinical Characteristics and Subtypes on Amyloid Positivity in Patients with Amnestic Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Amyloid deposits in positron-emission tomography (PET) imaging of MCI patients imply a higher risk for advancing to dementia, with rates of 10%–15% yearly. The purpose of this study was to investigate the clinical characteristics of subgroups of amnestic MCI (aMCI) that may have a higher impact on amyloid positivity.METHODS: We recruited 136 aMCI patients. All patients underwent a 20-minute F-18 florbetaben or flutemetamol PET scan. We classified amyloid PET images as positive or negative according to a semi-quantitative method. We evaluated the amyloid positivity of subgroups of aMCI (early vs. late type, single vs. multiple amnestic type, verbal vs. verbal, and visual amnestic type), and compared baseline clinical characteristics including key risk factors, apolipoprotein E4 (apoE4) genotype, and neuropsychological assessments with amyloid positivity in aMCI.RESULTS: The amyloid positivity in total aMCI was 41%. The positivity rate according to subgroup of aMCI were as follow: Late aMCI (49%) vs. early aMCI (33%) (p=0.13), multiple aMCI (40%) vs. single aMCI (38%) (p=0.51), and verbal and visual aMCI (59%) vs. verbal aMCI (35%) (p=0.01), respectively. The mean age and the frequency of apoE4 allele of the amyloid-positive group was higher than that of the amyloid-negative group in aMCI (p< 0.01).CONCLUSIONS: We found that the amyloid positivity was related to patterns of clinical subtypes, characteristics, and risk factors in patients with aMCI.

A New Biological Definition of Alzheimer's Disease: Introduction of 2018 National Institute on Aging-Alzheimer's Association Research Framework

Diagnostic guidelines for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease (AD) were released by the National Institute on Aging and Alzheimer's Association (NIA-AA) in 2011. Promoted by the subsequent scientific progress, a unifying update, the ‘NIA-AA Research Framework', was published in 2018. This new research framework shifts the definition of AD from syndrome to biological construct based on biomarkers in living people. The biomarkers were grouped into β amyloid deposition (A), pathologic tau (T), and neurodegeneration (N) related, termed the ‘AT(N) classification system#x2019;, which could be extended with new biomarkers as they become available in the future. For the staging of cognitive impairment, three syndromal stages for observational studies and six numeric stages for clinical trials were also suggested. This biomarker-based classification combined with clinical staging is expected to enhance the understanding of AD as well as aid in precise targeting for interventional clinical trials. This review focused on the introduction of the new 2018 NIA-AA Research Framework. Although this framework has been proposed for research purposes, it is expected to be adopted into general clinical practice with thorough examination and validation in the future.

Primary Amyloidosis Localized to the Conjunctiva

PURPOSE: To report a case of primary amyloidosis localized to the conjunctiva. CASE SUMMARY: A 19-year-old male with a conjunctival mass and foreign body sensations in the right eye transferred from another hospital. A 0.5 × 2.5 cm reddish mass was present in the medial canthus of the right conjunctiva with no other clinically specific signs. Surgical excisional biopsy was performed. Histological examination showed amyloid deposition. There was no other orbital involvement apart from the conjunctiva. Abnormalities were not found in the systemic examination. CONCLUSIONS: We report a case of primary amyloidosis localized to the conjunctiva.

Magnetic Resonance-Guided Focused Ultrasound : Current Status and Future Perspectives in Thermal Ablation and Blood-Brain Barrier Opening

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson's disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer’s disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.

The Cortical Neuroanatomy Related to Specific Neuropsychological Deficits in Alzheimer's Continuum

BACKGROUND AND PURPOSE: In Alzheimer's continuum (a comprehensive of preclinical Alzheimer's disease [AD], mild cognitive impairment [MCI] due to AD, and AD dementia), cognitive dysfunctions are often related to cortical atrophy in specific brain regions. The purpose of this study was to investigate the association between anatomical pattern of cortical atrophy and specific neuropsychological deficits. METHODS: A total of 249 participants with Alzheimer's continuum (125 AD dementia, 103 MCI due to AD, and 21 preclinical AD) who were confirmed to be positive for amyloid deposits were collected from the memory disorder clinic in the department of neurology at Samsung Medical Center in Korea between September 2013 and March 2018. To analyze neuropsychological test-specific neural correlates representing the relationship between cortical atrophy measured by cortical thickness and performance in specific neuropsychological tests, a linear regression analysis was performed. Two neural correlates acquired by 2 different standardized scores in neuropsychological tests were also compared. RESULTS: Cortical atrophy in several specific brain regions was associated with most neuropsychological deficits, including digit span backward, naming, drawing-copying, verbal and visual recall, semantic fluency, phonemic fluency, and response inhibition. There were a few differences between 2 neural correlates obtained by different z-scores. CONCLUSIONS: The poor performance of most neuropsychological tests is closely related to cortical thinning in specific brain areas in Alzheimer's continuum. Therefore, the brain atrophy pattern in patients with Alzheimer's continuum can be predict by an accurate analysis of neuropsychological tests in clinical practice.

Contributing Factors to Diabetic Brain Injury and Cognitive Decline

The link of diabetes with co-occurring disorders in the brain involves complex and multifactorial pathways. Genetically engineered rodents that express familial Alzheimer's disease-associated mutant forms of amyloid precursor protein and presenilin 1 (PSEN1) genes provided invaluable insights into the mechanisms and consequences of amyloid deposition in the brain. Adding diabetes factors (obesity, insulin impairment) to these animal models to predict success in translation to clinic have proven useful at some extent only. Here, we focus on contributing factors to diabetic brain injury with the aim of identifying appropriate animal models that can be used to mechanistically dissect the pathophysiology of diabetes-associated cognitive dysfunction and how diabetes medications may influence the development and progression of cognitive decline in humans with diabetes.

The First Generation of iPSC Line from a Korean Alzheimer's Disease Patient Carrying APP-V715M Mutation Exhibits a Distinct Mitochondrial Dysfunction

Alzheimer's Disease (AD) is a progressive neurodegenerative disease, which is pathologically defined by the accumulation of amyloid plaques and hyper-phosphorylated tau aggregates in the brain. Mitochondrial dysfunction is also a prominent feature in AD, and the extracellular Aβ and phosphorylated tau result in the impaired mitochondrial dynamics. In this study, we generated an induced pluripotent stem cell (iPSC) line from an AD patient with amyloid precursor protein (APP) mutation (Val715Met; APP-V715M) for the first time. We demonstrated that both extracellular and intracellular levels of Aβ were dramatically increased in the APP-V715M iPSC-derived neurons. Furthermore, the APP-V715M iPSC-derived neurons exhibited high expression levels of phosphorylated tau (AT8), which was also detected in the soma and neurites by immunocytochemistry. We next investigated mitochondrial dynamics in the iPSC-derived neurons using Mito-tracker, which showed a significant decrease of anterograde and retrograde velocity in the APP-V715M iPSC-derived neurons. We also found that as the Aβ and tau pathology accumulates, fusion-related protein Mfn1 was decreased, whereas fission-related protein DRP1 was increased in the APP-V715M iPSC-derived neurons, compared with the control group. Taken together, we established the first iPSC line derived from an AD patient carrying APP-V715M mutation and showed that this iPSC-derived neurons exhibited typical AD pathological features, including a distinct mitochondrial dysfunction.

Magnetic Resonance-Guided Focused Ultrasound : Current Status and Future Perspectives in Thermal Ablation and Blood-Brain Barrier Opening

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson's disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer’s disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.

Re-transmissibility of mouse-adapted ME7 scrapie strain to ovine PrP transgenic mice

Scrapie is a mammalian transmissible spongiform encephalopathy or prion disease that predominantly affects sheep and goats. Scrapie has been shown to overcome the species barrier via experimental infection of other rodents. To confirm the re-transmissibility of the mouse-adapted ME7 scrapie strain to ovine prion protein (PrP) transgenic mice, mice of an ovinized transgenic mouse line carrying the Suffolk sheep PrP gene that contained the A₁₃₆ R₁₅₄ Q₁₇₁/ARQ allele were intracerebrally inoculated with brain homogenates obtained from terminally ill ME7-infected C57BL/6J mice. Herein, we report that the mouse-adapted ME7 scrapie strain was successfully re-transmitted to the transgenic mice expressing ovine PrP. In addition, we observed changes in the incubation period, glycoform profile, and pattern of scrapie PrP (PrP(Sc)) deposition in the affected brains. PrP(Sc) deposition in the hippocampal region of the brain of 2nd-passaged ovine PrP transgenic mice was accompanied by plaque formation. These results reveal that the mouse-adapted ME7 scrapie strain has the capacity to act as a template for the conversion of ovine normal monomeric precursors into a pathogenic form in ovine PrP transgenic mice. The change in glycoform pattern and the deposition of plaques in the hippocampal region of the brain of the 2nd-passaged PrP transgenic mice are most likely cellular PrP species dependent rather than being ME7 scrapie strain encoded.

Cerebral Amyloid Quantification in Cognitively Normal Korean Adults Using F-18 Florbetaben PET / 대한핵의학회잡지

PURPOSE: To investigate regional cerebral amyloid beta retention in cognitively normal Korean adults using F-18 florbetaben (FBB).METHODS: We prospectively analyzed F-18 FBB positron emission tomography (PET)/CT scans of 30 cognitively healthy adults (age range, 50??0 years) using automated quantification. The standardized uptake value ratios (SUVRs) of F-18 FBB were calculated for predefined regions by normalizing the regional count with cerebellar cortex.RESULTS: The distribution of amyloid beta for each brain region revealed no age-related trends (p > 0.05). From all subjects, mean SUVR of amyloid deposit was 1.30 ± 0.18. The right parietal lobe showed the highest SUVR value (1.46 ± 0.23), whereas the right frontal lobe and left precuneus showed the lowest SUVR (1.23 ± 0.25).CONCLUSIONS: We provide reference values of normative data obtained from healthy elderly Koreans and suggest its use for accurate diagnosis of patients with Alzheimer's disease.

Amiloidosis sistémica, a propósito de un caso de autopsia / SYstemic Amyloidosis. About an autopsy case

During history, amylidosis was observed associated to a great variety of inflammatory diseases, and due to this, appeared the term "secondary amyloidosis". The forms of sudden presentation without any apparent cause are classified as "primary amyloidosis", and also the localized amyloidosis was characterized, the same as the heredity variant. At present, three main grops are recognized as systemic amyloidosis: amyloidosis of light chains, the amyloidosis associated to the seric protein A, and the hereditary form. Systemic amyloidosis can involve practically any organ system, being the most commonly affected the heart and the kidney, which therefore determine the clinical evolution and the prognosis of the patient. The aim of this report, was to present a case of autopsy of systemic amyloidosis with involvement of the Central Nervous System, considering besides, the great extension of the disease in our patient

Asymptomatic Localized Gastric Amyloidosis with Two Separate Lesions

Amyloidosis is a disease in which amyloid is abnormally accumulated in the tissue. The kidney and heart are the most commonly involved organs. Gastric involvement is relatively common in systemic disease; however, localized gastric amyloidosis is rare. Here, we report a case of localized gastric amyloidosis with two separate lesions. A 56-year-old woman underwent a health surveillance checkup without any noticeable symptoms. She was under medication for diabetes and dyslipidemia, and was otherwise healthy. On surveillance upper endoscopy, an irregularly shaped hyperemic elevated erosion at the gastric fundus and a 1.5-cm, yellowish subepithelial tumor-like lesion with intact overlying mucosa at the lesser curvature of the lower body of the stomach were detected. Endoscopic biopsy revealed submucosal eosinophilic material deposition in both lesions. Congo-red staining showed amyloid deposit appearing as a yellow-green birefringence under polarizing microscopy. Echocardiography, abdominal sonography, and colonoscopy revealed no abnormality. The patient was diagnosed as having localized gastric amyloidosis and is now undergoing regular follow-up without any treatment. Localized gastric amyloidosis is a rare disease that may mimic nonspecific gastritis or subepithelial tumor. However, endoscopic biopsy with appropriate staining may be diagnostic and thorough evaluation for systemic involvement is important.

A Case of Amyloidosis Presenting as Lymphadenopathy at the Porta Hepatis

We report a rare case of systemic amyloidosis with gastrointestinal and lymph node involvement. A 64-year-old woman was admitted to our hospital with dyspepsia and weight loss. Initial esophagogastroduodenoscopy (EGD) revealed nonspecific findings, and abdominal computed tomography showed necrotizing lymphadenopathy at the porta hepatis. Laparoscopic lymph node biopsy was performed under suspicion of tuberculous lymphadenopathy, but a definite diagnosis was not established. Follow-up EGD performed 6 months later revealed multiple telangiectasia-like lesions at the gastric body, and endoscopic biopsy revealed amyloid deposition. Through additional blood and urine protein electrophoresis, the patient was finally diagnosed with systemic amyloidosis associated with multiple myeloma. She was treated with dexamethasone, thalidomide, and bortezomib; however, she died 3 months after diagnosis because of pneumonia and multiple organ failure.

Reproduction,genotype identification and evaluation of APP/PS1 transgenic mice / 中国应用生理学杂志

OBJECTIVES@#To identify the genotype of (APP/PS1) transgenic mice and evaluate the changing of cognitive and behavioral fu nctions, provide an effective animal model for the Alzheimer's disease (AD) research.@*METHODS@#Male APP/PS1 transgenic mice mated with female APP/PS1 transgenic mice, and the genotype of their filial mice was identified by PCR. The APP +/PS1 + mice were assigned into AD model group (AD group, =8), and the APP/PS1 mice were assigned into control group (CT group, =8). The Morris water maze test was carried out to detect the capacity of learning and memory of mice. After that, the mice were sacrificed and the brain tissues were sampled and stained by HE and congo red for the pathological examination.@*RESULTS@#①A APP/PS1 genome DNA about 360 bp size was detected. The methods of feeding and breeding were successful to attain APP/PS1 transgenic mice.②Statistical significance was found in the differences of the capacity of learning and memory between 7-month-old APP/PS1 positive mice and negative mice (<0.05).③The results of HE stain showed that the structure and cellular morphology of hippocampus of AD mice were obviously abnormal. The results of congo red stain showed that positive amyloid plaque was observed in brains of AD mice.@*CONCLUSIONS@#APP/PS1 transgenic mice present typical symptoms and behaviors of Alzheimer's disease. The transgenic mouse is an effective tool for the research and prevention of AD.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.