Lung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of... Show moreLung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of immunotherapy in 2015, this survival has increased significantly, with the first results showing a survival of even a few years. However, the response rate is relatively low, the treatment is expensive and the (low percentage of) side effects are severe. Therefore a biomarker is needed to predict which patients would benefit of immunotherapy.This thesis is about the search for a new biomarker. With the use of the RNA of platelets, proteins, tumor markers in blood and a an electronic nose for exhaled breath, we tried to find a non-invasive biomarker for the prediction of response on immunotherapy and for the (future) use in clinical practice, some of which are promising. Show less
Hummelink, K.; Noort, V. van der; Muller, M.; Schouten, R.D.; Lalezari, F.; Peters, D.; ... ; Thommen, D.S. 2022
Purpose: Durable clinical benefit to PD-1 blockade in non- small cell lung cancer (NSCLC) is currently limited to a small fraction of patients, underlining the need for predictive biomar-kers. We... Show morePurpose: Durable clinical benefit to PD-1 blockade in non- small cell lung cancer (NSCLC) is currently limited to a small fraction of patients, underlining the need for predictive biomar-kers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-1T TILs as biomarker in NSCLC. Experimental Design: PD-1T TILs were digitally quantified in 120 baseline samples from advanced NSCLC patients treated with PD-1 blockade. Primary outcome was disease control (DC) at 6 months. Secondary outcomes were DC at 12 months and survival. Exploratory analyses addressed the impact of lesion-specific responses, tissue sample properties, and combination with other biomarkers on the predictive value of PD-1T TILs. Results: PD-1T TILs as a biomarker reached 77% sensitivity and 67% specificity at 6 months, and 93% and 65% at 12 months,respectively. Particularly, a patient group without clinical benefit was reliably identified, indicated by a high negative predictive value (NPV) (88% at 6 months, 98% at 12 months). High PD-1T TILs related to significantly longer progression-free (HR 0.39, 95% CI, 0.24-0.63, P < 0.0001) and overall survival (HR 0.46, 95% CI, 0.28-0.76, P < 0.01). Predictive performance was increased when lesion-specific responses and samples obtained immediately before treatment were assessed. Notably, the pre-dictive performance of PD-1T TILs was superior to PD-L1 and tertiary lymphoid structures in the same cohort. Conclusions: This study established PD-1T TILs as predictive biomarker for clinical benefit to PD-1 blockade in patients with advanced NSCLC. Most importantly, the high NPV demon-strates an accurate identification of a patient group without benefit. Show less
Objectives: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing... Show moreObjectives: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing experience, this global consensus document summarizes key management recommendations. Methods: International experts with experience in the management of patients with ongoing HVAD support were invited to summarize key aspects of patient and pump management and highlight differences in the current HeartMate 3 (Abbott Laboratories) ventricular assist device. Clinicians from high-implanting HVAD sites reviewed current literature and reported experience to generate a consensus statement. Results: Specific guidelines to assist in the management of ongoing HVAD patients are developed. Key management protocols and helpful techniques developed from experienced clinicians are combined into a short guideline document. As experience with HeartMate 3 increases, key differences in approach to management are highlighted, where appropriate. Conclusions: With decreasing worldwide experience in the ongoing management of HVAD-supported patients, this consensus guideline provides a summary of best practice techniques from international centers. Differences in HeartMate 3 management are highlighted. Show less
In't Veld, S.G.J.G.; Arkani, M.; Post, E.; Antunes-Ferreira, M.; D'Ambrosi, S.; Vessies, D.C.L.; ... ; Wurdinger, T. 2022
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising... Show moreCancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening. Show less
Buma, A.I.G.; Muller, M.; Vries, R. de; Sterk, P.J.; Noort, V. van der; Wolf-Lansdorf, M.; ... ; Heuvel, M.M. van den 2021
Objectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma ... Show moreObjectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma (NSCLC). We hypothesized that the eNose could also be used as an early monitoring tool to identify responders more accurately at early stage of treatment when compared to baseline. In this proof-of-concept study we aimed to definitely discriminate responders from non-responders after six weeks of treatment. Materials and Methods: This was a prospective observational study in patients with advanced NSCLC eligible for anti-PD-1 treatment. The efficacy of treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. We analyzed SpiroNose exhaled breath data of 94 patients (training cohort n = 62, validation cohort n = 32). Data analysis involved signal processing and statistics based on Independent Samples T-tests and Linear Discriminant Analysis (LDA) followed by Receiver Operating Characteristic (ROC) analysis. Results: In the training cohort, a specificity of 73% was obtained at a 100% sensitivity level to identify objective responders. The Area Under the Curve (AUC) was 0.95 (CI: 0.89-1.00). In the validation cohort, these results were confirmed with an AUC of 0.97 (CI: 0.91-1.00). Conclusion: Exhaled breath analysis by eNose early during treatment allows for a highly accurate, non-invasive and low-cost identification of advanced NSCLC patients who benefit from anti-PD-1 therapy. Show less
Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase... Show moreBackground The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Optimizing emergency care for the aging population is an important future challenge, as the proportion of older patients at the emergency department (ED) rapidly increases. Older patients,... Show moreOptimizing emergency care for the aging population is an important future challenge, as the proportion of older patients at the emergency department (ED) rapidly increases. Older patients, particularly those who are frail, have a high risk of adverse outcomes after an ED visit, such as functional decline, institutionalization, and death. The ED can have a key position in identifying frail older patients who benefit most from comprehensive geriatric care [including delirium preventive measures, early evaluation of after-discharge care, and a comprehensive geriatric assessment (CGA)]. However, performing extensive frailty assessment is not suitable at the ED. Therefore, quick and easy-to-use instruments are needed to identify older patients at risk for adverse outcomes. This narrative review outlines the importance and complexity of frailty assessment at the ED. It aligns the available screening instruments, including clinical judgment as frailty assessment, and summarizes arguments for and against frailty assessment at the ED. Show less
Tet3 is the main alpha -ketoglutarate (alpha KG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess... Show moreTet3 is the main alpha -ketoglutarate (alpha KG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How alpha KG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into alpha KG in an NAD(+)-dependent manner, is redirected to the nucleus by the alpha KG-consumer protein Tet3, suggesting on-site production of alpha KG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of alpha KG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity. alpha -ketoglutarate (alpha KG) is an intermediate in the tricarboxylic acid cycle that is required in the nucleus for genomic DNA demethylation by Tet3. Here, the authors show that the enzyme glutamate dehydrogenase, which converts glutamate to alpha KG, is redirected from the mitochondria to the nucleus. Show less
Aims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70... Show moreAims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70 years in four geographical risk regions.Methods and results Sex-specific competing risk-adjusted models for estimating CVD risk (CVD mortality, myocardial infarction, or stroke) were derived in individuals aged over 65 without pre-existing atherosclerotic CVD from the Cohort of Norway (28 503 individuals, 10 089 CVD events). Models included age, smoking status, diabetes, systolic blood pressure, and total- and high-density lipoprotein cholesterol. Four geographical risk regions were defined based on country-specific CVD mortality rates. Models were recalibrated to each region using region-specific estimated CVD incidence rates and risk factor distributions. For external validation, we analysed data from 6 additional study populations {338 615 individuals, 33 219 CVD validation cohorts, C-indices ranged between 0.63 [95% confidence interval (CI) 0.61-0.65] and 0.67 (0.64-0.69)}. Regional calibration of expected-vs.-observed risks was satisfactory. For given risk factor profiles, there was substantial variation across the four risk regions in the estimated 10-year CVD event risk.Conclusions The competing risk-adjusted SCORE2-OP model was derived, recalibrated, and externally validated to estimate 5- and 10-year CVD risk in older adults (aged 70 years or older) in four geographical risk regions. These models can be used for communicating the risk of CVD and potential benefit from risk factor treatment and may facilitate shared decision-making between clinicians and patients in CVD risk management in older persons. Show less
BackgroundCheckpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging... Show moreBackgroundCheckpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging offers distinctive advantages, providing whole-body information non-invasively, while routinely available in most clinics. We hypothesized that more prognostic information can be extracted by employing artificial intelligence (AI) for treatment monitoring, superior to 2D tumor growth criteria.MethodsA cohort of 152 stage-IV non-small-cell lung cancer patients (NSCLC) (73 discovery, 79 test, 903CTs), who received nivolumab were retrospectively collected. We trained a neural network to identify morphological changes on chest CT acquired during patients' follow-ups. A classifier was employed to link imaging features learned by the network with overall survival.ResultsOur results showed significant performance in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.69 (p < 0.01), up to AUC 0.75 (p < 0.01) in the first 3 to 5 months of treatment, and 0.67 AUC (p = 0.01) for durable clinical benefit (6 months progression-free survival). We found the AI-derived survival score to be independent of clinical, radiological, PDL1, and histopathological factors. Visual analysis of AI-generated prognostic heatmaps revealed relative prognostic importance of morphological nodal changes in the mediastinum, supraclavicular, and hilar regions, lung and bone metastases, as well as pleural effusions, atelectasis, and consolidations.ConclusionsOur results demonstrate that deep learning can quantify tumor- and non-tumor-related morphological changes important for prognostication on serial imaging. Further investigation should focus on the implementation of this technique beyond thoracic imaging. Show less
Verheijen, R.B.; Duijl, T.T. van; Heuvel, M.M. van den; Vessies, D.; Muller, M.; Beijnen, J.H.; ... ; Huitema, A.D.R. 2021
Purpose We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated... Show morePurpose We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. Methods The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. Results In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. Conclusion This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression. Show less
Barone, M.; Muller, M.; Chiha, S.; Ren, J.; Albat, D.; Soicke, A.; ... ; Kuhne, R. 2020
Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular... Show moreBattling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein-protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined prolinederived modules (ProMs) to succeed in developing a nanomolar inhibitor (K-d = 120 nM, MW = 734 Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the sup pression of cancer metastasis by inhibiting a crucial protein- protein interaction involved in actin filament processing and cell migration. Show less
Schouten, R.D.; Egberink, L.; Muller, M.; Gooijer, C.J. de; Werkhoven, E. van; Heuvel, M.M. van den; Baas, P. 2020
Background: For advanced non-small cell lung cancer anti-PD-1 treatment has become standard care in first and second line treatment in recent years. Because many of the clinical trials with anti-PD... Show moreBackground: For advanced non-small cell lung cancer anti-PD-1 treatment has become standard care in first and second line treatment in recent years. Because many of the clinical trials with anti-PD-1 drugs have only recently been completed, long term follow up data of patients treated with these agents is scarce, even more so of patients treated in real life clinical care. We present long term follow up of patients treated with nivolumab.Methods: Two hundred forty-eight patients with pre-treated, advanced NSCLC who received nivolumab between August 2015 and December 2018 were included in this retrospective cohort study. Overall survival and progression free survival rates were calculated for the total cohort and for subgroups defined by clinical characteristics, responses to treatment, and other parameters. Data on further lines of treatment and characteristics of long term survivors were also collected.Results: Median overall survival in the total cohort was 8.1 months, median progression free survival was 2.8 months. Overall survival after two and three years was 23.8% and 17.1%, respectively. Good ECOG performance scores, absence of liver metastases, experiencing treatment-related toxicity, and response to nivolumab were significantly associated with longer overall survival and progression free survival. Three-year survival rate among patients with an objective response was 55.3%. Survival for more than two years without subsequent therapy after nivolumab was observed in 13.3% of patients.Conclusions: The results from our study confirm that long term survival rates of patients treated with nivolumab for advanced NSCLC in a real world clinical setting are comparable to survival rates shown in clinical trials. Show less
Purpose: Pretreatment selection of patients with non-small cell lung cancer (NSCLC) who would derive clinical benefit from treatment with immune checkpoint inhibitors (CPIs) would fulfill an unmet... Show morePurpose: Pretreatment selection of patients with non-small cell lung cancer (NSCLC) who would derive clinical benefit from treatment with immune checkpoint inhibitors (CPIs) would fulfill an unmet clinical need by reducing unnecessary toxicities from treatment and result in substantial health care savings.Experimental Design: In a retrospective study, mass spectrometry (MS)-based proteomic analysis was performed on pretreatment sera derived from patients with advanced NSCLC treated with nivolumab as part of routine clinical care (n = 289). Machine learning combined spectral and clinical data to stratify patients into three groups with good ("sensitive"), intermediate, and poor ("resistant") outcomes following treatment in the second-line setting. The test was applied to three independent patient cohorts and its biology was investigated using protein set enrichment analyses (PSEA).Results: A signature consisting of 274 MS features derived from a development set of 116 patients was associated with progression-free survival (PFS) and overall survival (OS) across two validation cohorts (N = 98 and N = 75). In pooled analysis, significantly better OS was demonstrated for "sensitive" relative to "not sensitive" patients treated with nivolumab; HR, 0.58 ( 95% confidence interval, 0.38-0-87; P = 0.009). There was no significant association with clinical factors including PD-L1 expression, available from 133 of 289 patients. The test demonstrated no significant association with PFS or OS in a historical cohort (n = 68) of second-line NSCLC patients treated with docetaxel. PSEA revealed proteomic classification to be significantly associated with complement and woundhealing cascades.Conclusions: This serum-derived protein signature successfully stratified outcomes in cohorts of patients with advanced NSCLC treated with second-line PD-1 CPIs and deserves further prospective study. Show less
Objective Consistent with the aging population in the Western world, there is agrowing number of elderly patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous... Show moreObjective Consistent with the aging population in the Western world, there is agrowing number of elderly patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) is the recommended reperfusion strategy in elderly patients; risk models to determine which of these patients are prone to have poor clinical outcomes are, however, essential. The purpose of this study was to assess the association between frailty and short-term mortality and PCI-related serious adverse events (SAE) in elderly patients.Methods All STEMI patients (aged >= 70 years) treated with primary PCI in 2013-2015 at the Leiden University Medical Centre were assessed. The Safety Management Programme (VMS) score was used to identify frail elderly patients. The primary endpoint was 30-day all-cause mortality; the secondary endpoint included 30-day clinical death, target vessel failure, major bleeding, contrast induced kidney insufficiency and stroke.Results A total of 206 patients were included (796.4 years, 119 [58%] male). The VMS score was 1 in 28% of all cases. Primary and secondary endpoint rates were 5 and 23% respectively. VMS score 1 was an independent predictor for both 30-day mortality (odds ratio [OR] 9.6 [95% confidence interval, CI 1.6-56.9] p-value = 0.013) and 30-day SAE (OR 2.9 [95% CI 1.1-7.9] p-value = 0.038).Conclusions VMS score for frailty is independently associated with short-term mortality and PCI-related SAE in elderly patients with STEMI treated with primary PCI. These results suggest that frailty in elderly patients is an important feature to measure and to be taken into account when developing risk models. Show less
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently... Show moreIncreasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. Show less
