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Different subsets of Alzheimer's disease neuropathologic change (ADNC), including the intriguing set of individuals with severe/widespread amyloid-β (Aβ) plaques but no/mild tau tangles [Aβ-predominant (AP)-ADNC], may have distinct genetic and clinical features. Analysing National Alzheimer's Coordinating Center data, we stratified 1187 participants into AP-ADNC (n = 95), low Braak primary age-related tauopathy (PART; n = 185), typical-ADNC (n = 832) and high-Braak PART (n = 75). AP-ADNC differed in some clinical features and genetic polymorphisms in the APOE, SNX1, WNT3/MAPT and IGH genes. We conclude that AP-ADNC differs from classical ADNC with implications for in vivo studies.

BackgroundApolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.MethodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau.ResultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.ConclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

OBJECTIVE: Excess cholesterol loading on arterial macrophages is linked to foam cell formation, atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). However, the effect of changes in cholesterol loading on coronary plaque trajectory and the impact of RA therapies on this relationship are unknown. We investigated the association between variations in cholesterol loading capacity (CLC) over time and atherosclerosis progression. METHODS: In a prospective observational cohort study, coronary CT angiography evaluated atherosclerosis (non-calcified, partially calcified or fully calcified plaques and coronary artery calcium (CAC) score) in 100 patients with RA without cardiovascular disease at baseline and 6.9±0.4 years later. The presence of ≥5 plaques and lesions rendering >50% stenosis was considered an extensive and obstructive disease, respectively. Serum CLC was measured on human THP-1 monocyte-derived macrophages with a fluorometric assay. RESULTS: Mean CLC change (follow-up CLC-baseline CLC) was 1.54 (SD 3.69) μg cholesterol/mg protein. In models adjusting for atherosclerotic cardiovascular disease risk score, baseline plaque and other relevant covariates, CLC change (per SD unit increase) is associated with a higher likelihood of progression of non-calcified (OR 2.55, 95% CI 1.22 to 5.35), fully calcified plaque (OR 3.10, 95% CI 1.67 to 5.76), CAC (OR 1.80, 95% CI 1.18 to 2.74) and new extensive or obstructive disease (OR 2.43, 95% CI 1.11 to 5.34). Exposure to prednisone unfavourably influenced, while biologics and statins favourably affected the relationship between CLC change and atherosclerosis progression (all p-for-interactions ≤0.048). CONCLUSION: CLC change is associated with atherosclerosis progression in a dose-dependent manner, including lipid-rich non-calcified plaques and extensive or obstructive disease that yield the greatest cardiovascular risk.

BackgroundStudies on cannabis use and adverse cardiovascular outcomes have reported conflicting results. Research on its relationship to calcified arterial plaque remains limited.MethodsCross-sectional data from 2152 participants at Exam 6 (2016-2018) in the Multi-Ethnic Study of Atherosclerosis (MESA) were analyzed, including self-reported cannabis smoking patterns and carotid artery calcification (CAC) as measured via computed tomography. Multivariable relative and absolute risk regression models were used to estimate adjusted prevalence ratios (PRs) and prevalence differences, respectively, for the presence of calcified plaque. Multivariable linear regression was then used to compare group differences in the extent of CAC in those with calcified plaque.ResultsA minority of participants (n = 159, 7.4%) reported a history of regular cannabis smoking. Among all participants, 36.1% (n = 777) had detectable CAC. In models adjusted for demographics, behavioral, and clinical cardiovascular disease factors, a history of regular cannabis smoking was not associated with the prevalence of CAC in either common carotid artery (PR: 1.14, 95% CI: 0.88 to 1.49). In the subset of participants with calcified plaque, and in separate fully adjusted multivariable linear regression models, a history of regular cannabis smoking was not associated with increased calcium volume (difference = 7.7%, 95% CI: -21.8 to 48.5), calcium density (difference = 0.4%, 95% CI: -6.6 to 7.9), or Agatston score (difference = 32.1%, 95% CI: -31.8 to 155.8) in either carotid artery. Models exploring potential effect modification by age, race/ethnicity, and tobacco smoking status showed no significant association, except for higher CAC prevalence in men with a history of regular cannabis smoking.ConclusionsIn a racially and ethnically diverse cohort of older adults with a moderately high prevalence of CAC, no associations were found between a history of regular cannabis smoking, duration, or recency of cannabis smoking, and the prevalence of carotid calcified plaque. These findings were consistent across age, race/ethnicity, and cigarette smoking, except for an increased prevalence in men with a history of regular cannabis smoking. Similarly, in a subgroup with CAC, no association was found between a history of regular cannabis smoking and extent of calcification as measured by volume, density, and Agatston score.

Systemic amyloidosis involves the deposition of misfolded proteins in organs/tissues, leading to progressive organ dysfunction and failure. Congo red is the gold-standard chemical stain for visualizing amyloid deposits in tissue, showing birefringence under polarization microscopy. However, Congo red staining is tedious and costly to perform, and prone to false diagnoses due to variations in amyloid amount, staining quality and manual examination of tissue under a polarization microscope. We report virtual birefringence imaging and virtual Congo red staining of label-free human tissue to show that a single neural network can transform autofluorescence images of label-free tissue into brightfield and polarized microscopy images, matching their histochemically stained versions. Blind testing with quantitative metrics and pathologist evaluations on cardiac tissue showed that our virtually stained polarization and brightfield images highlight amyloid patterns in a consistent manner, mitigating challenges due to variations in chemical staining quality and manual imaging processes in the clinical workflow.

BACKGROUND: Increases in low-density lipoprotein cholesterol (LDL-C) can occur on carbohydrate restricted ketogenic diets. Lean metabolically healthy individuals with a low triglyceride-to-high-density lipoprotein cholesterol ratio appear particularly susceptible, giving rise to the novel lean mass hyper-responder (LMHR) phenotype. OBJECTIVES: The purpose of the study was to assess coronary plaque burden in LMHR and near-LMHR individuals with LDL-C ≥190 mg/dL (ketogenic diet [KETO]) compared to matched controls with lower LDL-C from the Miami Heart (MiHeart) cohort. METHODS: There were 80 KETO individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL, high-density lipoprotein cholesterol ≥60 mg/dL, and triglyceride levels ≤80 mg/dL, without familial hypercholesterolemia, matched 1:1 with MiHeart subjects for age, gender, race, hyperlipidemia, hypertension, and smoking status. Coronary artery calcium and coronary computed tomography angiography (CCTA) were used to compare coronary plaque between groups and correlate LDL-C to plaque levels. RESULTS: The matched mean age was 55.5 years, with a mean LDL-C of 272 (maximum LDL-C of 591) mg/dl and a mean 4.7-year duration on a KETO. There was no significant difference in coronary plaque burden in the KETO group as compared to MiHeart controls (mean LDL 123 mg/dL): coronary artery calcium score (median 0 [IQR: 0-56]) vs (1 [IQR: 0-49]) (P = 0.520) CCTA total plaque score (0 [IQR: 0-2] vs [IQR: 0-4]) (P = 0.357). There was also no correlation between LDL-C level and CCTA coronary plaque. CONCLUSIONS: Coronary plaque in metabolically healthy individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL on KETO for a mean of 4.7 years is not greater than a matched cohort with 149 mg/dL lower average LDL-C. There is no association between LDL-C and plaque burden in either cohort. (Diet-induced Elevations in LDL-C and Progression of Atherosclerosis [Keto-CTA]; NCT057333255).

Purpose To clarify the predominant causative plaque constituent for periprocedural myocardial injury (PMI) following percutaneous coronary intervention: (a) erythrocyte-derived materials, indicated by a high plaque-to-myocardium signal intensity ratio (PMR) at coronary atherosclerosis T1-weighted characterization (CATCH) MRI, or (b) lipids, represented by a high maximum 4-mm lipid core burden index (maxLCBI4 mm) at near-infrared spectroscopy intravascular US (NIRS-IVUS). Materials and Methods This retrospective study included consecutive patients who underwent CATCH MRI before elective NIRS-IVUS-guided percutaneous coronary intervention at two facilities. PMI was defined as post-percutaneous coronary intervention troponin T values greater than five times the upper reference limit. Multivariable analysis was performed to identify predictors of PMI. Finally, the predictive capabilities of MRI, NIRS-IVUS, and their combination were compared. Results A total of 103 lesions from 103 patients (median age, 72 years [IQR, 64-78]; 78 male patients) were included. PMI occurred in 36 lesions. In multivariable analysis, PMR emerged as the strongest predictor (P = .001), whereas maxLCBI4 mm was not a significant predictor (P = .07). When PMR was excluded from the analysis, maxLCBI4 mm emerged as the sole independent predictor (P = .02). The combination of MRI and NIRS-IVUS yielded the largest area under the receiver operating curve (0.86 [95% CI: 0.64, 0.83]), surpassing that of NIRS-IVUS alone (0.75 [95% CI: 0.64, 0.83]; P = .02) or MRI alone (0.80 [95% CI: 0.68, 0.88]; P = .30). Conclusion Erythrocyte-derived materials in plaques, represented by a high PMR at CATCH MRI, were strongly associated with PMI independent of lipids. MRI may play a crucial role in predicting PMI by offering unique pathologic insights into plaques, distinct from those provided by NIRS. Keywords: Coronary Plaque, Periprocedural Myocardial Injury, MRI, Near-Infrared Spectroscopy Intravascular US Supplemental material is available for this article. © RSNA, 2024.

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Objectives: The prevalence and the economic burden of periodontal disease are high. To save or replace diseased teeth, an objective prognosis assessment using the long-term predictability of the various treatment options should be performed. As dental implants have become a treatment of choice for replacing missing teeth, the number of implant failures and complications has also increased. The objective of this review was to compare the cost-effectiveness of saving and maintaining the teeth vs replacing them with dental implants in patients with severe periodontal disease (with hopeless or questionable teeth). Method and materials: A database search was conducted using Medline (OVID), Embase, Web of Science, and CINAHL electronic sources until July 2023. Two reviewers reviewed the papers in accordance with the specific selection criteria after choosing the abstracts that met the initial selection criterion for full article retrieval. Results: Twelve articles were included, of which nine articles discussed the cost-effectiveness of preserving teeth in severe periodontal disease and three articles discussed the effectiveness of implants that replaced the periodontally compromised teeth. It was found that placing and maintaining implants was more costly than properly treating and maintaining periodontally compromised teeth. Supportive periodontal treatment contributed the most to the cost during the periodontal treatment. Conclusions: Implants are an effective choice to replace missing teeth; however, these are not permanent, present complications, and require strict maintenance. Thus, when deciding whether to maintain a periodontally compromised tooth or to replace it with a dental implant, in terms of cost-effectiveness, implant maintenance cost as well as the cost associated with treating implant complications should be considered. This cost seems to surpass the cost of treatment and maintenance of periodontally compromised teeth. [ABSTRACT FROM AUTHOR]

Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies. We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology. Male New Zealand White rabbits (n = 16) were placed on a high-fat diet, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68Ga-DOTATATE, 18F-NaF, and 18F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal-corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histology. Analyses were performed blindly. EIS impedance was associated with markers of plaque activity including macrophage infiltration (r = .813, p = .008) and macrophage/smooth muscle cell (SMC) ratio (r = .813, p = .026). Moreover, EIS phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r = .883, p = .004) and %stenosis (r = .901, p = .002), similar to IVUS. 68Ga-DOTATATE correlated with intimal macrophage infiltration (r = .861, p = .003) and macrophage/SMC ratio (r = .831, p = .021), 18F-NaF with SMC infiltration (r = -.842, p = .018), and 18F-FDG correlated with macrophage/SMC ratio (r = .787, p = .036). EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS to comprehensively evaluate human coronary artery disease.

Clinical risk scores based on traditional risk factors of atherosclerosis correlate imprecisely to an individuals complex pathophysiological predisposition to atherosclerosis and provide limited accuracy for predicting major adverse cardiovascular events (MACE). Over the past two decades, computed tomography scanners and techniques for coronary computed tomography angiography (CCTA) analysis have substantially improved, enabling more precise atherosclerotic plaque quantification and characterization. The accuracy of CCTA for quantifying stenosis and atherosclerosis has been validated in numerous multicentre studies and has shown consistent incremental prognostic value for MACE over the clinical risk spectrum in different populations. Serial CCTA studies have advanced our understanding of vascular biology and atherosclerotic disease progression. The direct disease visualization of CCTA has the potential to be used synergistically with indirect markers of risk to significantly improve prevention of MACE, pending large-scale randomized evaluation.

BACKGROUND: In Alzheimers disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

IntroductionThe BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.MethodsTo elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.ResultsThe presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.DiscussionThe BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.HighlightsBIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

The absence of a natural animal model is one of the main challenges in Alzheimers disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimers disease.

Atherosclerosis, previously regarded as a lipid storage disease, has now been classified as a chronic inflammatory disease. The hardening of arterial vessels characterizes atherosclerosis due to the accumulation of lipids in the arterial walls, eliciting an inflammatory response. The development of atherosclerosis occurs in various stages and is facilitated by many clinical factors, such as hypertension, hyperlipidemia, and inflammatory status. A large arsenal of cells has been implicated in its development. This review will summarize the phases of atherosclerotic formation and all the cells involved in either promoting or inhibiting its development. [ABSTRACT FROM AUTHOR]

Determining the mechanical characteristics of the artery is very essential for the production of vascular implants. In the present work, the mechanical characteristics of arterial walls were investigated by considering plaque and stent in a 3D model. This article aims to investigate the effect of the arterial tissue with the same boundary conditions and restrictions for an artery blocked with the plaque and stent, in creating stress in the tissue. An intravascular stent implantation is a treatment method whose success largely depends on the mechanical characteristics of each vascular component, plaque and stent, and blood flow pressure. For opening up the blood flow in the blocked artery, stents could be used as medical devices. In this research, a stent was designed, and its impact on all three models of elastic, viscoelastic, and hyper-elastic arterial tissue with plaque was studied and compared. An ideal finite element model was made to find the effect of three types of the artery tissue (elastic, viscoelastic, hyper-elastic) with the systolic and diastolic blood flow pressure to observe the stress and the deformation of arteries, plaques, and stents. In addition, for the hyper-elastic model, two Mooney-Rivlin and Ogden models were also investigated. It was found that the type of artery had an effective impact on the result of the stress and the deformation created in the stented artery. Moreover, the results illustrated that considering different models for the artery tissue affected the plaque and stent behavior. Arteries exhibit interesting mechanical behaviors. In the present study, an attempt was made to investigate different mechanical behaviors of arteries with the plaque and stent obstruction. In the examined models, the stress for the artery and plaque was higher in the Ogden model and the lowest one was in the viscoelastic model, and the deformation was higher in the viscoelastic model and lower in the Ogden model. It should be noted that the average stress for the vessel in the Ogden model was about 50% higher than the viscoelastic model. Pathological changes in the walls of the vessels can lead to high-risk cardiovascular diseases such as heart attacks and strokes. Understanding arterial mechanical behaviors provides valuable insight into disease. Therefore, the investigation of different behavioral models helps to evaluate the behavior of the arterial wall by considering the composition and function of the tissue. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the effects of subgingival ozonated water irrigation as an adjunct to non-surgical periodontal treatment on clinical and biochemical parameters of patients with moderate and severe periodontitis. A total of 72 Stage II and III periodontitis patients were included in the study. The 72 systemically healthy patients were treated non-surgically. Finally of each visit concerning periodontal treatment, the pocket of each tooth was irrigated with a sterile plastic syringe (10 mL per quadrant) with a blunt tip containing ozonated water (OW; ozone groups), 0.12% chlorhexidine (CHX groups) or saline (C; control groups) for 30-60s. Periodontal clinical parameters, gingival crevicular fluid (GCF), vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) levels were evaluated at baseline and 8 weeks after therapy. GI and PPD values of Stage II periodontitis patients and the PPD values of Stage III periodontitis patients were lower in the OW group compared with the CHX and C groups, showing statistical difference (p < 0.05). The beneficial impact of subgingival OW applications VEGF and IGF levels, which are thought to play a role in the pathogenesis of periodontal disease and periodontal regeneration, should be taken into consideration. [ABSTRACT FROM AUTHOR]

Background/Objectives: The accumulation of uric acid in arteriosclerotic plaques has recently attracted attention. Because the interaction between hyperuricemia and atherosclerosis is complex, the details remain obscure. We aimed to elucidate the clinical effect of monosodium urate monohydrate (MSU) deposition on carotid plaques. Methods: This study enrolled 89 patients with carotid plaques. MSU deposits were confirmed using Gomori's methenamine silver staining of carotid endarterectomy (CEA) specimens. To evaluate the macrophage and microvessel marker counts, we used CD68 and CD31. Plaque composition was investigated in carotid plaques with MSU deposition and inflammation. We also examined the use of dual-energy computed tomography (DECT) and compensated for pathological findings to detect MSU crystal deposition in carotid plaques. Results: Of the 89 patients who underwent CEA, 31 (34.8%) had hyperuricemia. Overall, 22 (24.7%) participants had MSU deposits and 67 (75.3%) did not. MSU deposits, CD31-positive microvessels, and CD68-positive cells were observed in shoulder lesions. The number of CD31-positive microvessels and CD68-positive cells was higher in patients with MSU deposits than in those without MSU deposits. Most plaques expressing MSU were plaques with intraplaque hemorrhage. The consistency in MSU deposit identification between histopathology and DECT was poor (kappa = 0.34). Conclusions: MSU deposition may be related to the inflammation of carotid plaques. [ABSTRACT FROM AUTHOR]

Background: Oral diseases such as caries, gingivitis, and periodontitis are highly prevalent worldwide and often arise from plaque. This study focuses on detecting three plaque stages—new, mature, and over-mature—using state-of-the-art YOLO architectures to enhance early intervention and reduce reliance on manual visual assessments. Methods: We compiled a dataset of 531 RGB images from 177 individuals, captured via multiple mobile devices. Each sample was treated with disclosing gel to highlight plaque types, then preprocessed for lighting and color normalization. YOLOv9, YOLOv10, and YOLOv11, in various scales, were trained to detect plaque categories, and their performance was evaluated using precision, recall, and mean Average Precision (mAP@50). Results: Among the tested models, YOLOv11m achieved the highest mAP@50 (0.713), displaying superior detection of over-mature plaque. Across all YOLO variants, older plaque was generally easier to detect than newer plaque, which can blend with gingival tissue. Applying the O'Leary index indicated that over half of the study population exhibited severe plaque levels. Conclusions: Our findings demonstrate the feasibility of automated plaque detection with advanced YOLO models in varied imaging conditions. This approach offers potential to optimize clinical workflows, support early diagnoses, and mitigate oral health burdens in low-resource communities. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease is the leading causes of death and disability worldwide. Intracranial atherosclerotic stenosis (ICAS) is one of the major causes of ischemic stroke, especially in the Asian population. It is urgent to explore effective screening methods for early diagnosis to improve prognosis of patients with ICAS. Recently, the concept of panvascular medicine has provided a direction for the exploration of evaluation of ICAS. Based on the concept of "panvascular medicine," atherosclerosis is the common pathological feature of panvascular disease, such as ICAS and coronary artery disease (CAD). In-depth research on the formation and development of plaques, the development and application of more precise preoperative assessment and detection methods, and the utilization of new interventional equipment have greatly enhanced the precision of diagnosis and treatment of CAD. Studies attempt to apply similar evaluation and treatment in ICAS. The deeper understanding, the more accurate diagnosis and treatment, contributing to improve the prognosis of patients with ICAS. This review focuses on these evaluations and treatment of CAD applied in the field of ICAS. [ABSTRACT FROM AUTHOR]

In this article, we focus on kynurenic acid metabolism in neuropsychiatric disorders and the biochemical processes involved in memory and cognitive impairment, followed by different approaches in the fight against dementia. Kynurenic acid—a biochemical part of L-tryptophan catabolism—is synthesized from L-kynurenine by kynurenine aminotransferases. Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferases opens new therapeutic avenues for the treatment of memory impairment and dementia. The newly developed Helix pomatia snail model of memory can be used for the assessment of novel pharmacological approaches. Dietary supplementation with natural molecular/herbal extracts, exercise, and physical activity have significant impacts on endogenous pharmacology by reducing kynurenic acid synthesis, and these factors are likely to significantly modulate steady-state biological conditions and delay the negative consequences of aging, including the onset of pathological processes. [ABSTRACT FROM AUTHOR]

The broad spectrum of clinical manifestations caused by peripheral arterial disease [PAD] and the morphologic heterogeneity of associated atherosclerotic lesions present a considerable management challenge. Endovascular interventions are recognized an effective treatment for PAD. Within this revascularization strategy the role of atherectomy debulking modalities continue to evolve. Accordingly, the study herein assessed the efficacy and safety of a novel, solid state, Nd: YAG pulsed-wave [355 nm wavelength] laser atherectomy in the treatment of symptomatic infra-inguinal PAD. The EX-PAD-01 study, a prospective, single-arm, open label trial enrolled 50 patients (38 males, 12 females; mean age 64 years] with symptomatic peripheral arterial disease, who underwent percutaneous revascularization with a novel, solid state, pulsed-wave [355 nm wavelength] laser atherectomy followed with adjunct treatment. The Ankle-brachial index [ABI], Rutherford classification for chronic limb ischemia and the walking impairment questionnaire [WIQ] were used for assessment of the index clinical condition of the enrolled patients, for post procedure evaluation and during follow-up. Accordingly, the patients were followed for 12-months with repeated direct physician contact visits. Fifty-three atherosclerotic stenoses (51 femoropopliteal, 2 tibial) with a mean length of 7.4 cm. (ranged 1cm to 25cm) were treated. There were 79% occlusions, and 61% containing moderate-to-severe calcifications. The pre-procedure stenosis was 95.3 ± 10.3%, the Rutherford classification for chronic limb ischemia [CLI] was 2.90 ± 0.54 ranging between 2–4 and the WIQ 34.6 ± 8.62. Technical success was achieved in 52 of the 53 (98%) target lesions. Following laser debulking the baseline stenosis was reduced from 95.3 ± 10.3% to 61.3 ± 25.5% [ [p < 0.0001] and with adjunct balloon/stenting to final of 14.0 ± 14.0% [p < 0.0001]. Embolic protection devices were utilized in 6 [12%] patients. At 30-day post procedure evaluation the ABI increased from baseline of 0.57 ± 0.14 to 0.94 ± 0.14 [p < 0.0001] and no major adverse effects or device adverse effects were detected. At 6 months follow -up the ABI was 0.84 ± 0.20% (p < 0.0001 vs. initial) and at 1 year follow-up 0.79 ± 0.16 (P = 0.0001 vs. initial) without major adverse events. Out of 46 [92%] patients who reached the 12 months follow-up mark, 2 [4.3%] experienced clinically driven target lesion revascularization. Sustained clinical benefit for up to 12 months post procedure was demonstrated through documentation of statistically significant decrease of Rutherford CLI class as well as concomitant improvement in WIQ score and an increase of ABI value. The primary patency rate, as defined by peak systolic velocity ratio (PSVR) of < 2.5m/second was 95.7% (22 of 23) and 81.8% (18 of 22) at 6 months and 12 months, respectively. In an early European clinical experience with a series of 50 patients with symptomatic peripheral arterial disease, the novel Nd: YAG solid state, pulsed- wave 355nm cardiovascular laser atherectomy device provided effective and safe revascularization treatment. Follow-up at 6 and 12 months, respectively, substantiate the efficacy, safety profile and clinical merits of this novel laser. Thus, this device is useful in the management of select patients with symptomatic infra-inguinal atherosclerotic lesions. Clinical Trial Registration: Clinical trials.gov number: NTC02556255. [ABSTRACT FROM AUTHOR]

Summary Coronary computed tomography angiography (CCTA) is a well‐established and reliable non‐invasive imaging modality that provides a comprehensive assessment of coronary artery anatomy and luminal stenosis due to atherosclerosis. Owing to advances in CCTA software and technology, the composition and morphology of coronary plaque can be accurately evaluated. Adverse features which identify plaque as being high‐risk or ‘vulnerable’ can provide a personalised cardiovascular risk assessment over and above stenosis severity. High‐risk plaque features on CCTA include spotty calcification, low attenuation plaque, positive remodelling and the napkin ring sign. However, it can be challenging to characterise high‐risk plaque accurately on CCTA, and as such, education and experience are required. In this pictorial essay, a comprehensive visual guide to high‐risk plaque features on CCTA is provided, with clear examples and challenging cases that highlight common pitfalls. It is important for expert readers to properly identify these features given their association with adverse outcomes and potential future implications on intensive goal‐directed medical therapy. [ABSTRACT FROM AUTHOR]

Clusters of similar or dissimilar objects are encountered in many fields. Frequently used approaches treat each cluster's central object as latent. Yet, often objects of one or more types cluster around objects of another type. Such arrangements are common in biomedical images of cells, in which nearby cell types likely interact. Quantifying spatial relationships may elucidate biological mechanisms. Parent‐offspring statistical frameworks can be usefully applied even when central objects ("parents") differ from peripheral ones ("offspring"). We propose the novel multivariate cluster point process (MCPP) to quantify multi‐object (e.g., multi‐cellular) arrangements. Unlike commonly used approaches, the MCPP exploits locations of the central parent object in clusters. It accounts for possibly multilayered, multivariate clustering. The model formulation requires specification of which object types function as cluster centers and which reside peripherally. If such information is unknown, the relative roles of object types may be explored by comparing fit of different models via the deviance information criterion (DIC). In simulated data, we compared a series of models' DIC; the MCPP correctly identified simulated relationships. It also produced more accurate and precise parameter estimates than the classical univariate Neyman–Scott process model. We also used the MCPP to quantify proposed configurations and explore new ones in human dental plaque biofilm image data. MCPP models quantified simultaneous clustering of Streptococcus and Porphyromonas around Corynebacterium and of Pasteurellaceae around Streptococcus and successfully captured hypothesized structures for all taxa. Further exploration suggested the presence of clustering between Fusobacterium and Leptotrichia, a previously unreported relationship. [ABSTRACT FROM AUTHOR]

ABSTRACT: Introduction: Periodontal diseases (PDs) pose a significant challenge to dental health, leading to a growing interest in probiotics as potential therapeutic and prophylactic agents. Literature evidence has shown conflicting results on the use of probiotics in the management of PDs. Hence, this systematic review was performed to explore the effectiveness of probiotics in both the prevention and treatment of PDs by synthesizing data from relevant studies. Methodology: Various databases were searched using appropriate MeSH keywords as per the PRISMA protocol. Studies were included only if they met certain criteria. Two reviewers independently extracted data variables from the included literature. The risk of bias 2.0 tool was employed to assess the methodological quality of the included studies. Results: In total, 21 studies were considered eligible and included in the review. It was observed that 17 studies reported a statistically significant improvement in both periodontitis and gingivitis among the probiotic group compared to control cohorts. The synthesized evidence from the review suggests that probiotics play a favourable role in both the prevention and treatment of PDs. Conclusion: It also supports the incorporation of probiotics as a potential adjunctive therapy in PD management. However, further research is warranted to explore the specific probiotic strains, dosages, and treatment durations for optimized outcomes. [ABSTRACT FROM AUTHOR]

The objective was to evaluate using unstimulated saliva in detecting Aggregatibacter actinomycetemcomitans and to compare the saliva and subgingival and mucosa membrane occurrence of this periodontal pathogen in patients diagnosed with advanced periodontitis. Patients with advanced forms of periodontitis (n = 220; mean age: 54.03 ± 03 years) at stage III/IV were sampled. Unstimulated saliva, buccal cheek mucosa, and pooled subgingival plaque samples were collected. The identification of A. actinomycetemcomitans was performed using qPCR. A descriptive analysis and Wilcoxon test and analysis of variance were performed. A. actinomycetemcomitans was isolated from 28.18% of the subjects. A total of 660 samples were obtained, 220 from unstimulated saliva, 220 from buccal cheek mucosa surfaces, and 220 from pooled subgingival plaque samples. A. actinomycetemcomitans was isolated from 21.80% of unstimulated saliva, 19.50% of buccal cheek swabs, and 17.70% of subgingival samples. There was a statistically significant difference between the presence of A. actinomycetemcomitans in the unstimulated saliva samples and in the buccal cheek mucosa swab samples and pooled subgingival plaque samples (p < 0.001). These results suggest that in advanced periodontitis, unstimulated saliva is representative of pooled subgingival plaque/buccal cheek mucosa samples and its use is adequate in the oral detection of A. actinomycetemcomitans in a cohort of patients with stage III and IV periodontitis. [ABSTRACT FROM AUTHOR]

Context Current evidence of cardiovascular (CV) risk in primary hyperparathyroidism (PHPT) is still inconsistent. Objective To prospectively investigate changes of early atherosclerosis in patients with PHPT undergoing parathyroidectomy (PTx) or conservative management, according to consensus criteria. Methods Biochemical parameters of PHPT, CV risk factors (systolic and diastolic blood pressure, cholesterol [total, high-density, and low-density], triglyceride, HbA1c, HOMA-IR), and carotid intima-media thickness (IMT) and plaque were assessed in 52 consecutive postmenopausal PHPT patients both at baseline and ≥ 24 months after surgery (PTx, n = 22) or conservative management (non-PTx, n = 30). Results At baseline, PTx and non-PTx showed comparable age, BMI, renal function, and 25(OH)D levels, and did not differ for CV risk factors, IMT and plaques, or for prevalence of smoking, diabetes mellitus, or antihypertensive or statin therapy, while all parameters characterizing PHPT differed. Follow-up duration in PTx was longer than in non-PTx (P =.004). Parameters characterizing PHPT significantly improved ≥ 24 months after surgery, whereas in non-PTx serum phosphate slightly decreased and parathyroid hormone increased. Systolic and diastolic blood pressure increased at follow-up in both groups, while other CV risk factors did not significantly vary. In PTx, IMT did not significantly vary after surgery (0.85 ± 0.14 to 0.89 ± 0.22 mm, P =.366), whereas it significantly increased in non-PTx (0.80 ± 0.18 to 0.93 ± 0.23 mm, P =.008), even adjusting for blood pressure. Plaque prevalence and incidence did not significantly differ in the 2 groups. Conclusion Our results suggest that in postmenopausal patients with PHPT, subclinical atherosclerosis could be halted by PTx, whereas it worsens over time in nonoperated patients with milder disease. [ABSTRACT FROM AUTHOR]

Background: Orthodontic appliances hinder proper oral hygiene, leading to plaque retention and biofilm formation which can cause dental diseases. This study investigates the initial impact of orthodontic treatment with fixed appliances versus clear aligners on microbial profiles and gingival/plaque indices. Methods: Nine patients were included in this small-scale prospective longitudinal pilot study – five in treatment with fixed appliances and four with clear aligners. Plaque biofilm samples were collected subgingivally, supragingivally and from clear aligner trays, and gingival and plaque indices were recorded at six timepoints over 3 months. DNA was extracted and next-generation 16S rRNA sequencing of the V4 region was performed. Results: Fixed appliance patients showed higher plaque and gingival index scores early on (p ≤ 0.05) and higher levels of oral pathogens (p ≤ 0.05). Microbiological analysis revealed distinct microbial communities on clear aligner trays, with health- and disease-associated microbes present at significantly different levels (p ≤ 0.05) compared to intraoral plaque samples. Conclusions: Patients undergoing orthodontic therapy with fixed appliances had higher levels of plaque retention and oral pathogens. Clear aligner patients' had microbial profiles with more oral health-associated species and lower gingival/plaque indices. However, the biofilm on clear aligner trays requires further study, and the small sample size limits the conclusiveness of all findings. Implications: Dentists may consider clear aligners as an alternative to fixed appliances, with potential benefits in plaque accumulation and oral microbial composition. All patients undergoing orthodontic therapy should practice good oral hygiene to prevent plaque retention and reduce oral pathogen colonization. Continuing Education Credit Available: A CDA Continuing Education quiz is online for this article: The practice worksheet is available online: [ABSTRACT FROM AUTHOR]

Objectives: The effective control of dental plaque is crucial for oral health, given that pathogenic bacteria in plaque are the primary cause of dental caries. Current antimicrobial agents, although effective, disrupt the oral microbiome and lead to oral dysbiosis, hindering efforts to curb dental caries. Novel antimicrobial peptides offer a promising solution due to their selective bactericidal activity against cariogenic bacteria. This study explores the initial safety and efficacy of KSL‐W formulated into chewing gum through a Phase 1 and 2a clinical trial. Methods: The combined trial, approved by the FDA, follows a double‐blind, randomized, placebo‐controlled design. Phase 1 assessed safety with single doses (2−100 mg), whereas Phase 2a explored both safety and proof of concept in reducing oral bacteria with multiple doses (4−75 mg). Besides adverse events (Phase 1), outcome measures included whole‐mouth plaque and gingival index scores and bleeding on probing (Phase 2a). Results: KSL‐W demonstrated safety in both phases, with no severe adverse events. The proof‐of‐concept analysis revealed a decrease in plaque and gingival inflammation, particularly at doses ≥ 20 mg. The 30 mg dose appeared to yield optimal effects without any adverse reactions in subjects. Conclusions: Results from this study indicate that KSL‐W is safe for use in humans and provides initial evidence of its potential efficacy in reducing plaque and gingival inflammation. Further research is essential to determine optimal usage and ultimate safety, and to assess its potential in diverse populations. Trial Registration: The trial is registered with the FDA (Trial Registration Number: NCT01877421). The clinical trials were registered in the clinicaltrials.gov database under the title "Safety and Tolerability of Antiplaque Chewing Gum in a Gingivitis Population" and the identifier number is NCT01877421. The URL for accessing the study in clinicaltrials.gov is https://clinicaltrials.gov/study/NCT01877421?intr=Antiplaque%20chewing&rank=1. [ABSTRACT FROM AUTHOR]

Background/Objectives: The aim was to evaluate the agreement between plaque detection with an intraoral scanner system (IOS) and a conventional clinical method and to evaluate the inter-rater reliability for scoring 3D models with and without a disclosing agent. Methods: A total of 14 participants were recruited from the Department of Operative Dentistry, School of Dentistry, National and Kapodistrian University of Athens. Participants eligible for inclusion were adults with good general health and a minimum of 20 teeth. Participants were clinically examined with plaque assessment according to the modified Quigley–Hein plaque index before and after using a disclosing agent (GC-Tri Plaque ID-Gel, GC, Europe N.V). Before and after the application of the disclosing agent, all study participants were scanned using the IOS (TRIOS5, 3Shape TRIOS A/S). The clinical examiner and three additional examiners blinded to the clinical examination assessed plaque status on the acquired 3D models with and without disclosing agent using the same index to evaluate the inter-rater agreement. Intraclass coefficient correlation, one sample t-test, and Cronbach's α for inter-rater reliability were calculated. Results: All methods showed moderate to strong correlations (Spearman's rho ranging from 0.527 to 0.618), and Cronbach's α ranged from 0.551 to 0.766. Conclusions: The level of agreement between conventional clinical registration and registration from 3D models was acceptable overall. [ABSTRACT FROM AUTHOR]

Introduction: Proper plaque removal is necessary for oral hygiene. Since plaque is invisible, patients need to be educated about it by making it visible using disclosing solution. Due to limitations of disclosing solution, alternative methods are required to detect plaque and create awareness among patients. The objective of the study was to evaluate and compare the ability of plaque detection of fluorescence plaque detecting system Q scan with the traditionally used plaque disclosing solution. Methodology: The study was conducted on 174 undergraduate students of a dental institute after obtaining informed consent. The plaque level was first assessed and recorded by Quigley-Hein plaque index in each patient using fluorescent Q SCAN plus device and later using disclosing solution. All the participants were then asked to fill the questionnaire about their experience of plaque detection method. Results: The results of the study showed that the plaque score recorded using Q scan plus fluorescent plaque detecting system was significantly lower than that of the plaque scores recorded by the applying disclosing solution (P ≤ 0.05). Most of the students preferred the use of Q-scan plus fluorescent plaque detecting system for the evaluation of plaque level. Conclusion: It can be concluded from the results of the study that the Q-scan plus fluorescent plaque detecting system although took lesser time and is easy to use and convenient method of plaque detection is not as sensitive as disclosing solution.

It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

BACKGROUND: Transthyretin amyloidosis (ATTR) is a significant cause of cardiomyopathy and other morbidities in the elderly and Black Americans. ATTR can be treated with new disease-modifying therapies, but large shortfalls exist in its diagnosis. The objective of this study was to test whether TTR amyloid can be detected and imaged in the conjunctiva using a novel small-molecule fluorescent ocular tracer, with the implication that ATTR might be diagnosable by a simple eye examination. METHODS: Three approaches were used in this study. First, AMDX-9101 was incubated with in vitro aggregated TTR protein, and changes in its excitation and emission spectra were quantified. Second, a cadaver eye from a patient with familial amyloid polyneuropathy type II TTR mutation and a vitrectomy sample from an hATTR patient were incubated with AMDX-9101 and counterstained with Congo Red and antibodies to TTR to determine whether AMDX-9101 labels disease-related TTR amyloid deposits in human conjunctiva and eye. Last, imaging of in vitro aggregated TTR amyloid labeled with AMDX-9101 was tested in a porcine ex vivo model, using a widely available clinical ophthalmic imaging device. RESULTS: AMDX-9101 hyper-fluoresced in the presence of TTR amyloid in vitro, labeled TTR amyloid deposits in postmortem human conjunctiva and other ocular tissues and could be detected under the conjunctiva of a porcine eye using commercially available ophthalmic imaging equipment. CONCLUSIONS: AMDX-9101 enabled detection of TTR amyloid in the conjunctiva, and the fluorescent binding signal can be visualized using commercially available ophthalmic imaging equipment. TRANSLATIONAL RELEVANCE: AMDX-9101 detection of TTR amyloid may provide a potential new and noninvasive test for ATTR that could lead to earlier ATTR diagnosis, as well as facilitate development of new therapeutics.

INTRODUCTION: Anti-amyloid therapies are at the forefront of efforts to treat Alzheimers disease (AD). Identifying amyloid risk factors may aid screening and intervention strategies. While veterans face increased exposure to risk factors, whether they face a greater neuropathologic amyloid burden is not well understood. METHODS: Male decedents donating to two Alzheimers Disease Research Center (ADRC) brain banks from 1986 to 2018 with categorized neuritic plaque density and neurofibrillary tangles (n = 597) were included. Using generalized ordered logistic regression we modeled each outcomes association with military history adjusting for age and death year. RESULTS: Having served in the military (60% of sample) is associated with post mortem neuritic amyloid plaque (for each comparison of higher to lower C scores OR = 1.26; 95% confidence interval [CI] = 1.06-1.49) and tau pathology (B score OR = 1.10; 95% CI = 1.08-1.12). DISCUSSION: This is the first study, to our knowledge, finding increased levels of verified AD neuropathology in those with military service. Targeted veteran AD therapies is a pressing need.

Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p

Coronary computed tomography angiography (CCTA) is a noninvasive imaging modality of cardiac structures and vasculature considered comparable to invasive coronary angiography for the evaluation of coronary artery disease (CAD) in several major cardiovascular guidelines. Conventional image acquisition, processing, and analysis of CCTA imaging have progressed significantly in the past decade through advances in technology, computation, and engineering. However, the advent of artificial intelligence (AI)-driven analysis of CCTA further drives past the limitations of conventional CCTA, allowing for greater achievements in speed, consistency, accuracy, and safety. AI-driven CCTA (AI-CCTA) has achieved a significant reduction in radiation exposure for patients, allowing for high-quality scans with sub-millisievert radiation doses. AI-CCTA has demonstrated comparable accuracy and consistency in manual coronary artery calcium scoring against expert human readers. An advantage over invasive coronary angiography, which provides luminal information only, CCTA allows for plaque characterization, providing detailed information on the quality of plaque and offering further prognosticative value for the management of CAD. Combined with AI, many recent studies demonstrate the efficacy, accuracy, efficiency, and precision of AI-driven analysis of CCTA imaging for the evaluation of CAD, including assessing degree stenosis, adverse plaque characteristics, and CT fractional flow reserve. The limitations of AI-CCTA include its early phase in investigation, the need for further improvements in AI modeling, possible medicolegal implications, and the need for further large-scale validation studies. Despite these limitations, AI-CCTA represents an important opportunity for improving cardiovascular care in an increasingly advanced and data-driven world of modern medicine.

BackgroundOne strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease.MethodsWe conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries.ResultsIn the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of

Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

PurposeInflamed, prone-to-rupture coronary plaques are an important cause of myocardial infarction and their early identification is crucial. Atherosclerotic plaques are characterized by overexpression of the type-2 somatostatin receptor (SST2) in activated macrophages. SST2 ligand imaging (e.g. with [68 Ga]Ga-DOTA-TOC) has shown promise in detecting and quantifying the inflammatory activity within atherosclerotic plaques. However, the sensitivity of standard axial field of view (SAFOV) PET scanners may be suboptimal for imaging coronary arteries. Long-axial field of view (LAFOV) PET/CT scanners may help overcome this limitation. We aim to assess the ability of [68 Ga]Ga-DOTA-TOC LAFOV-PET/CT in detecting calcified, SST2 overexpressing coronary artery plaques.MethodsIn this retrospective study, 108 oncological patients underwent [68 Ga]Ga-DOTA-TOC PET/CT on a LAFOV system. [68 Ga]Ga-DOTA-TOC uptake and calcifications in the coronary arteries were evaluated visually and semi-quantitatively. Data on patients' cardiac risk factors and coronary artery calcium score were also collected. Patients were followed up for 21.5 ± 3.4 months.ResultsA total of 66 patients (61.1%) presented with calcified coronary artery plaques. Of these, 32 patients had increased [68 Ga]Ga-DOTA-TOC uptake in at least one coronary vessel (TBR: 1.65 ± 0.53). Patients with single-vessel calcifications showed statistically significantly lower uptake (SUVmax 1.10 ± 0.28) compared to patients with two- (SUVmax 1.31 ± 0.29, p

Intracranial atherosclerotic disease (ICAD) is a common cause of ischaemic stroke and transient ischaemic attack (TIA) with a high recurrence rate. It is often referred to as intracranial atherosclerotic stenosis (ICAS), when the plaque has caused significant narrowing of the vessel lumen. The lesion is usually considered symptomatic ICAD/ICAS (sICAD/sICAS) when it has caused an ischaemic stroke or TIA. The severity of luminal stenosis has long been established as a prognostic factor for stroke relapse in sICAS. Yet, accumulating studies have also reported the important roles of plaque vulnerability, cerebral haemodynamics, collateral circulation, cerebral autoregulation and other factors in altering the stroke risks across patients with sICAS. In this review article, we focus on cerebral haemodynamics in sICAS. We reviewed imaging modalities/methods in assessing cerebral haemodynamics, the haemodynamic metrics provided by these methods and application of these methods in research and clinical practice. More importantly, we reviewed the significance of these haemodynamic features in governing the risk of stroke recurrence in sICAS. We also discussed other clinical implications of these haemodynamic features in sICAS, such as the associations with collateral recruitment and evolution of the lesion under medical treatment, and indications for more individualised blood pressure management for secondary stroke prevention. We then put forward some knowledge gaps and future directions on these topics.

BackgroundPericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population.MethodsIn this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates.ResultsAmong 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001).ConclusionsAmong PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.