Parametric imaging of dual-time window [18F]flutemetamol and [18F]florbetaben studies.

Optimal pharmacokinetic models for quantifying amyloid beta (Aß) burden using both [18F]flutemetamol and [18F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [18F]flutemetamol and [18F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [18F]flutemetamol (N=24) or [18F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90-110 min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aß-positive vs Aß-negative scans ([18F]flutemetamol: range AUC=0.96-0.97 [18F]florbetaben: range AUC=0.83-0.85). Outcome parameters of most methods were highly correlated with the reference method (R2≥0.87), while lowest correlation were observed for MRTM2 (R2=0.71-0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression.

Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study.

BACKGROUND: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. METHODS: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. RESULTS: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (ß = - 0.22, OR = 0.80, p < .05), more prior study visits (ß = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (ß = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PCresearch = 27.4%, PCclinical = 9.0%, X2 = 10.56, p = .001), and loss of research interest (PCclinical = 46.3%, PCresearch = 16.5%, X2 = 32.34, p < .001). CONCLUSIONS: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.

The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact.

Background: Amyloid-ß (Aß) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and 'Small and Medium-sized enterprises' (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. The AMYPAD studies: In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method. Results: AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BP ND ), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aß burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine. Future steps: The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Atrial electrical and structural changes associated with longstanding hypertension in humans: implications for the substrate for atrial fibrillation.

UNLABELLED: INTRODUCTION: Hypertension (HT) is the most common modifiable risk factor for atrial fibrillation (AF), yet little is known of the atrial effects of chronic HT in humans. We aimed to characterize the electrophysiologic (EP) and electroanatomic (EA) remodeling of the right atrium (RA) in patients with chronically treated systemic HT and left ventricular hypertrophy (LVH) without a history of AF. METHODS AND RESULTS: Twenty patients with (systolic BP 145 ± 10 mmHg) and without (BP 119 ± 11 mmHg, P < 0.01) systemic HT underwent detailed conventional EP and EA voltage and activation mapping. We measured RA refractoriness at the coronary sinus and high septum at cycle lengths (CLs) 600 and 450 ms, and RA conduction velocities, activation times, and voltages at a global and regional level at CLs 600 ms and 300 ms. HT was associated with slowing of global (73 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) and regional conduction velocity particularly in the posterior RA (70 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) at the crista terminalis (fractionation and double potentials in HT 72%± 4 vs 43%± 23 in controls, P = 0.04). Mean RA voltage was similar between the 2 groups, however HT was associated with an increase in areas of low voltage (<0.5 mV; HT 13% vs controls 9%, P = 0.04). Sustained AF was induced in 30% HT patients and no controls. CONCLUSION: Chronically treated systemic HT with LVH is accompanied by atrial remodeling characterized by: (i) global conduction slowing, (ii) regional conduction delay particularly at the crista terminalis, and (iii) increased AF inducibility. These changes may in part be responsible for the increased propensity to AF associated with systemic HT.

Diurnal Cortisol Secretion Is Not Related to Multiple Sclerosis-Related Fatigue.

Some evidence supports the involvement of the hypothalamic-pituitary-adrenal axis (HPA axis) with multiple sclerosis (MS)-related fatigue. In this study, we determined the relation of HPA-axis function with primary fatigue in MS patients in the longitudinal treating fatigue in a MS cohort. MS patients from the TREeating FAtigue in MS (TREFAMS) research program that consists of three randomized controlled trials to study the effects of aerobic training, energy conservation management, and cognitive behavioral therapy on MS-related fatigue were included. The HPA-axis functioning was determined at baseline, the end of treatment (16 weeks) and after 52 weeks. The cortisol awakening response (CAR) and night-time cortisol levels were analyzed. Fatigue was measured with the fatigue subscale of the Checklist Individual Strength (CIS20r fatigue). There was no relationship between CAR and night-time cortisol parameters with CIS20r fatigue scores. Neither of the treatments influenced CAR and night-time cortisol parameters, with the exception of an effect in the energy conservation management treatment group on the CAR surge increase over 52 weeks (ß = -114.8, p = 0.007, 95% CI = -197.6, -31.9). Our data suggest that the diurnal cortisol secretion is not associated with MS-related fatigue. This indicates that MS-related fatigue is not attributed to diurnal cortisol secretion and is likely caused by other disease mechanisms.