Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The relationship between C-reactive protein and depression in older adults: associations with incidence of type 2 diabetes mellitus

Background: Depression among older adults is a growing public health concern worldwide. However, the pathophysiological mechanisms remain elusive among older adults, where depression often occurs in co-morbidity with chronic medical conditions such as Type 2 diabetes mellitus (T2DM). Inflammation has been posited to be involved in depression and in diabetes. Evidence has shown that a higher concentration of C-reactive protein (CRP), a marker of inflammation, is associated with depressed mood and T2DM.Objectives: The first manuscript is a systematic review and meta-analysis that seeks to review and summarize the evidence on the relationship between CRP and depression in a general population of older adults (50 years and older). The second manuscript is a longitudinal study that aims to examine the bidirectional association of high CRP levels with elevated symptoms of depression among older adults. The third manuscript is a longitudinal study designed to assess the joint association of high CRP and depressive symptomatology with diabetes incidence in a community sample of older adults. Methods: The systematic review identified cross-sectional and longitudinal studies in scientific databases, and the meta-analysis was conducted using random-effects models. The two original research studies used data from the English Longitudinal Study of Ageing (ELSA), a prospective study of community-dwelling older adults. Logistic and Cox proportional hazard regressions were conducted while adjusting for socio-demographic, lifestyle, and clinical variables. Results: From the meta-analysis of cross-sectional studies, we observed a weak but positive correlation between CRP and depressive symptoms that was attenuated in the most adjusted model. From the meta-analysis of prospective studies, there was a small positive correlation between CRP levels at baseline and depressive symptoms at follow-up. In the first ELSA study, a high CRP level at baseline was associated with elevated depressive symptomatology at follow-up but was attenuated after adjusting for metabolic and co-morbidity factors. An association in the opposite direction was not observed. Lastly, older adults with both high CRP levels and elevated depressive symptoms were at risk for T2DM. Conclusion: The associations between depressed mood, diabetes, and CRP are complex and multifaceted. Higher CRP levels are associated with depressive symptomatology in a general population of older adults, but this association involves interplay with metabolic and chronic health conditions. Further research is required to broaden our understanding of the inflammation, depression, and diabetes relationship, thereby allowing opportunities for clinicians and researchers to explore new avenues for research, prevention, and treatment of these conditions.Contexte: La dépression parmi les personnes âgées est une préoccupation croissante de santé publique reconnue à l'échelle mondiale. Par contre, les mécanismes physiopathologiques parmi cette population qui expliquent la comorbidité entre la dépression et d'autres maladies chroniques, dont le diabète de type 2, ne sont toujours pas clairs pour les chercheurs. Il se pourrait que l'inflammation puisse expliquer cette association. Les données scientifiques indiquent qu'une concentration plus élevée de la protéine c-réactive (PCR), un marqueur de l'inflammation, est associée aux symptômes dépressifs et au diabète de type 2.Objectifs : Le premier manuscrit de ce mémoire est une revue systématique et une méta-analyse qui résume la recherche portant sur la relation entre la PCR et la dépression parmi une population générale de personnes âgées (50 ans et plus). Le deuxième manuscrit est une étude longitudinale qui vise à examiner la relation bidirectionnelle entre la PCR et les symptômes dépressifs élevés. Le troisième manuscrit est une étude longitudinale qui évalue l'association entre la PCR élevée, les symptômes dépressifs, et l'incidence de diabète de type 2 dans un échantillon communautaire d'adultes âgés. Méthodes: La revue systématique a identifié des études transversales et longitudinales parmi des bases de données scientifiques, et la méta-analyse a été menée en utilisant des modèles d'effets aléatoires. Les deux études longitudinales ont utilisé des données de l'étude English Longitudinal Study of Ageing (ELSA), une étude prospective d'adultes âgés habitant au sein de la communauté. Des régressions logistiques et à risque proportionnel de Cox ont été effectuées, et les modèles ont été ajustés pour des facteurs sociodémographiques, cliniques, et de style de vie.Résultats : La méta-analyse d'études transversales nous a permis d'observer une corrélation faible mais positive entre la PCR et les symptômes dépressifs. Cette corrélation fut atténuée lorsque le modèle fut ajusté pour tous les facteurs de confusion. La méta-analyse d'études prospectives a démontré une corrélation positive entre la PCR de base et les symptômes dépressifs observés lors d'examens de suivi. Dans la première sous-étude ELSA, les hauts niveaux de base de PCR étaient associés aux symptômes élevés de dépression lors d'examens de suivi, même en contrôlant pour les symptômes dépressifs de base, et pour les facteurs sociodémographiques, cliniques, et de style de vie. Une relation dans le sens opposé n'a pas été observée. Les adultes âgés ayant un haut niveau de PCR et de symptômes dépressifs avaient un risque élevé de développer le diabète de type 2. Conclusions: Les associations entre les symptômes dépressifs, le diabète, et la PCR sont complexes. De hauts niveaux de PCR sont associés avec les symptômes dépressifs, mais cette association interagie avec des facteurs métaboliques et des conditions chroniques de la santé. De la recherche supplémentaire est nécessaire afin d'approfondir nos connaissances sur la relation entre l'inflammation, la dépression et le diabète, ainsi que d'explorer de nouvelles avenues de recherche pour la prévention et le traitement de ces conditions

MECHANICAL AND BIOCHEMICAL FACTORS INFLUENCING INITIAL PLATELET ADHESION TO COLLAGEN: IMPORTANT ROLE FOR SLIDING AND ROLLING IN ACCELERATED AGGREGATE FORMATION

Injury at the vessel wall leads to exposure of collagen to which platelets initially adhere, grow into aggregates and eventually thrombotic masses which can occlude the vessel lumen. This process underlies the disorders of heart attack and stroke. The initial phase of platelet aggregation governs the extent of thrombus formation. We have investigated initial platelet attachment to collagen-coated surfaces under mechanical and biochemical conditions in a parallel plate flow reactor. A simple algorithm has been developed to simulate the effects of platelet sliding/rolling on the surface with respect to the development of surface aggregate formation. Platelets are hypothesized to stop such movement once they collide with a neighboring platelet in their pathway (due to platelet coherence that strengthens the overall adhesive forces due to platelet-platelet bonding). We and others have observed microscopically that platelets will either attach firmly onto the surface, roll and slide or detach completely from the surface. Platelet behavior was investigated for overall adhesion and the translocation dynamics on overall adhesion on temperature, flow conditions, C-reactive protein (CRP), and coffee consumption. Our findings indicate that temperature, shear force, and CRP promote platelet adhesion and the intake of coffee impedes platelet adhesion.M.S. in Biomedical Engineering, May 201

Effects of Acupuncture upon cerebral hemodynamics in cerebral small vessel disease: A pilot study

Background and aims: Recent preclinical studies and meta-analysis of clinical trials suggested that acupuncture may improve cognition in cerebral small vessel disease (CSVD). We investigated the cerebral hemodynamics of acupuncture in subjects with CSVD and compared its impact upon the cerebral hemodynamics in normal elderly subjects Methods: 10 subjects with CSVD (CSVD group) and 10 aged-matched control subjects who had no or insignificant CSVD (control group) were recruited. A single session of acupuncture was applied for 30 min in both groups. We assessed the effect of our acupuncture intervention on cerebral hemodynamics by transcranial Doppler ultrasound (TCD). Peak systolic velocity (PSV) and pulsatility index (PI) of the middle cerebral artery (MCA) were assessed Results: We observed that PSV increased by a maximum of 39% at 20 min (p<0.05), while there was no significant change in PI in the CSVD group during the acupuncture session. In the control group, although we observed no significant change in PSV during the acupuncture session, there was a significant decrease in PI by a maximum of 22% at 20 min (p<0.05). No adverse events were reported during or after the procedure. Conclusion: This study suggested that our acupuncture prescription was associated with an increase in cerebral blood flow in subjects with established moderate to severe CSVD yet without apparent impact on distal vascular resistance. While, in subjects with no or insignificant CSVD, it may reduce cerebral small vessel distal vascular resistance. A larger study is needed to confirm our findings

Kaplan-Meier Survival Curves stratified by depression-cardiometabolic groupings.

<p>DCM: comorbid high depressive symptoms and cardiometabolic abnormalities group; DnoCM: high depressive symptoms only group; noDCM: cardiometabolic abnormalities only group; noDnoCM: no or low depressive symptoms and no cardiometabolic abnormalities group.</p

Participant Flow Chart.

<p>DCM: comorbid high depressive symptoms and cardiometabolic abnormalities group; DnoCM: high depressive symptoms only group; noDCM: cardiometabolic abnormalities only group; noDnoCM: no or low depressive symptoms and no cardiometabolic abnormalities group; ELSA: English Longitudinal Study of Ageing.</p