#2977 Cognitive performance and affective symptoms in patients undergoing clinical Amyloid PET imaging

ObjectivesThe typical onset of Alzheimers Disease (AD) is characterised by episodic memory impairment. However, AD pathology can present with atypical clinical features and/or mixed aetiologies, which often lead to diagnostic uncertainty. Biomarker evaluation using amyloid PET imaging (API) in this group is guided by published appropriate use criteria (Johnson et al., 2013). A large proportion of these patients is also referred for clinical neuropsychological assessment. Here, we investigate the cognitive profiles and affective symptoms of memory clinic patients who are referred to both API and neuropsychological assessment as part of their diagnostic assessment.MethodsFrom a larger group of 396 patients that underwent clinical API between December 2013 and June 2019 at the Imperial Memory Clinic, we included individuals who also had a formal neuropsychological assessment (minimum of 4 domains) within 18 months of API and who received subsequent follow-up at our clinic. Referrals to API were in line with the appropriate use criteria and took place after multidisciplinary team discussion. A total of 107 patients, 47 amyloid-positive (Aβ-pos) and 60 amyloid-negative (Aβ-neg), were included. The Aβ-neg group was further divided into progressive (progAβ-neg, n=26) and stable (stableAβ-neg, n=34), based on the presence or absence of documented clinical progression and/or concomitant neurological condition.ResultsThe three groups were comparable for age and premorbid IQ, while there was a lower proportion of females in the stableAβ-neg group (table 1). ANCOVA models (with age, sex and premorbid IQ as covariates, and group as fixed factor) revealed that the Aβ-pos group performed worse than both negative groups in the domains of visuospatial and working memory (figure 1). The Aβ-pos group differed from the stableAβ-neg but not the progAβ-neg group on a measure of episodic memory (figure 1). The Hospital Anxiety and Depression scale (HADS) was administered to 85 patients (36 Aβ-pos, 20 progAβ-neg, 29 stableAβ-neg): non-parametric testing revealed higher levels of depressive symptoms in the stableAβ-neg group than in the Aβ-pos group (figure 2a). Notably, a significant proportion of patients reported clinical levels (HADS≥8) of anxiety and depression across all groups (figure 2b).Abstract #2977 Table 1Demographic and general characteristics of the study sampleAβ-posstableAβ-negprogAβ-negAgeyears,meanSD66.578.84 68.0310.48 66.588.71 PremorbidIQ,meanSD101.2712.3 101.9313.45 100.9611.95 Gender,%female61.70% 29.4% 50% Abstract #2977 Figure 1(A) Unadjusted mean raw anxiety and depression scores as measured by the HADS. *adjusted p<0.05; (B) Proportion of patients with clinically significant levels (HADS≥8) of anxiety and depression.Abstract #2977 Figure 2ConclusionsIn a memory clinic cohort undergoing clinical amyloid PET imaging and neuropsychological assessment, visuospatial dysfunction and working memory impairment were better indicators of Alzheimers pathology than episodic memory dysfunction. Moreover, in this group we found a high prevalence of anxiety and depressive symptoms regardless of amyloid status.Loreto et al. Cognitive performance and affective symptoms in patients undergoing clinical Amyloid PET Imaging

Prognostic Impact of 18-F-Florbetaben Amyloid PET Imaging in Patients with Isolated Increases in Cerebrospinal Fluid Phospho-Tau Biomarkers: A Longitudinal Study

This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer’s disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75%(6/8) for positive and 35%(6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

Background Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. Results Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.

Evaluating cognitive profiles of patients undergoing clinical amyloid-PET imaging

Episodic memory impairment and brain amyloid-beta are two of the main hallmarks of Alzheimer’s Disease. In the clinical setting, these are often evaluated through neuropsychological testing and amyloid PET imaging, respectively. The use of amyloid PET in clinical practice is only indicated in patients with substantial diagnostic uncertainty due to atypical clinical presentation, multiple comorbidities and/or early age of onset. The relationship between amyloid-beta and cognition has been previously investigated, but no study has examined how neuropsychological features relate to the presence of amyloid pathology in the clinical population that meets the appropriate use criteria for amyloid PET imaging. In this study, we evaluated a clinical cohort of patients (n = 107) who presented at the Imperial Memory Clinic and were referred for clinical amyloid PET and neuropsychological assessment as part of their diagnostic workup. We compared the cognitive performance of amyloid-positive patients (Aβ-pos, n = 47) with that of stable amyloid-negative (stableAβ-neg, n = 26) and progressive amyloid-negative (progAβ-neg, n = 34) patients. The amyloid-positive group performed significantly worse than both amyloid-negative groups in the visuospatial and working memory domains. Episodic memory performance, however, effectively differentiated the amyloid-positive group from the stable but not the progressive amyloid-negative group. On affective questionnaires, the stable amyloid-negative group reported significantly higher levels of depression than the amyloid-positive group. In our clinical cohort, visuospatial dysfunction and working memory impairment were better indicators of amyloid positivity than episodic memory dysfunction. These findings highlight the limited value of isolated cognitive scores in patients with atypical clinical presentation, comorbidities and/or early age of onset.

Amyloid PET imaging in clinical practice

Amyloid positron emission tomography (PET) imaging enables in vivo detection of brain Aβ deposition, one of the neuropathological hallmarks of Alzheimer’s disease. There is increasing evidence to support its clinical utility, with major studies showing that amyloid PET imaging improves diagnostic accuracy, increases diagnostic certainty and results in therapeutic changes. The Amyloid Imaging Taskforce has developed appropriate use criteria to guide clinicians by predefining certain scenarios where amyloid PET would be justified. This review provides a practical guide on how and when to use amyloid PET, based on the available research and our own experience. We discuss its three main appropriate indications and illustrate these with clinical cases. We stress the importance of a multidisciplinary approach when deciding who might benefit from amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in its interpretation.