Visual Read Research Articles

Can escapees of familial AD help identify protective factors? A case report of an extremely resilient PSEN1 carrier

AbstractBackgroundCarriers of mutations in PSEN1, PSEN2 or APP develop early‐onset Alzheimer’s dementia around a certain age depending on the specific mutation. However, some individuals “escape their fate”, meaning they remain asymptomatic far beyond their expected age at onset (EAO). We call these individuals “escapees”. A well‐known example is the resilient PSEN1 carrier that led to the identification of the protective APOEε3‐Christchurch mutation (Arboleda‐Velasquez et al., 2019). Here we present an extremely resilient PSEN1‐P264L mutation carrier where the cause of resilience has not yet been identified.MethodCarriers of PSEN1‐P264L have an EAO of 47 (SD = 4.3 years; Ryman et al., 2014). Our patient remains asymptomatic at age 58, which less than 0.6% of mutation carriers are expected to reach unaffected. We characterized this individual over the course of eight years with neuropsychological tests (n = 9), MRI scans (n = 5), amyloid (n = 3, [18F]florbetapir) and tau (n = 3, [18F]flortaucipir) PET scans and cerebrospinal fluid (CSF; n = 1). Genetic analysis of APOE and polygenic risk score (PRS) is described.ResultNeuropsychological test scores were within normal range at baseline and no significant cognitive decline was observed from age 50 to 58. On five consecutive MRI scans, no abnormalities or evidence of neurodegeneration was observed with visual read. At age 50, the patient was amyloid‐positive and tau‐positive in CSF (table 1). The patient was also amyloid‐positive on their first PET at age 51 (fig. 1). Widespread amyloid‐PET binding was observed, which increased over time. On tau‐PET, the patient was negative at age 51 and 53 (fig. 1), but positive at age 56, with an atypical binding pattern that shows high occipital load with relative sparing of the temporal and parietal cortex. This tau pattern and progression are remarkably similar to that seen in the escapee with the APOEε3‐Christchurch mutation. The APOE status of the patient is APOE ε3ε3 and the patient had an average PRS (+0.2SD from population average). Whole genome sequencing is ongoing.ConclusionWe describe an “escapee” of a PSEN1 mutation in which we have not yet identified the protective factor(s). Escapees represent rare but potent resilience phenotypes that should be studied systematically.

Harmonization of tau‐PET in Alzheimer’s disease: comparison of methods to derive CenTauR units for [18F]RO948, [18F]Flortaucipir, and [18F]MK‐6240

AbstractBackgroundTau positron emission tomography (PET) is increasingly used in the clinical evaluation of patients and as an outcome measure in Alzheimer’s disease (AD) clinical trials. Due to differences in tracer properties, instrumentation, and methods of analysis, however, tau‐PET outcome data cannot currently be meaningfully compared or combined. Here, we tested i) the feasibility of adapting the Centiloid method—an approach originally developed to standardize amyloid PET—to harmonize tau‐PET quantification (CenTauRs); ii) the performance of a non‐linear mixed model‐based approach (Joint Propagation Model) that does not require the use of a reference tracer.MethodHead‐to‐head tau‐PET data (Table 1) was included from two cohorts ([18F]RO948 vs [18F]flortaucipir, n = 37 [BioFINDER‐2]; [18F]flortaucipir [Avid A05] vs [18F]MK‐6240, n = 15, University of Pittsburgh) in which each participant was scanned with two tau‐PET tracers. Standardized uptake value ratio (SUVR) values were calculated using the inferior cerebellar cortex as the reference region. Anchor point data (Table 1) was derived for each tracer using the following criteria: CenTauR‐0, cognitively unimpaired (CU), amyloid PET negative (<10 Centiloids); CenTauR‐100, amyloid PET positive (>50 Centiloids), typical (temporoparietal) AD pattern on tau‐PET visual read, age<65 andMMSE>20. Regions‐of‐interest (ROIs) included a universal tau‐PET ROI—based on the intersection of tracer specific ([18F]flortaucipir, [18F]MK‐6240, [18F]PI‐2620, [18F]PM‐PBB3, [18F]GTP1 and [18F]RO948) masks that had been derived by subtracting average of amyloid‐negative CU images from the average AD image—as well as four subregions delineated within this ROI (medial temporal, meta‐temporal, temporoparietal and frontal) (Figure 1A). An overview of the adapted Centiloid‐like approach and the joint propagation model is shown in Figure 1B.ResultHigh R2 values were observed between tracers across all ROIs: [18F]RO948 vs [18F]flortaucipir, average 0.965 [range 0.923 (frontal) to 0.986 (universal)]; [18F]MK‐6240 vs [18F]flortaucipir, average 0.985 [range, 0.923 (medial temporal) to 0.991 (frontal)]. The Centiloid‐like and joint propagation model approaches provided near identical CenTauR values (Figure 2).ConclusionPreliminary findings support the development of standardized scale for tau‐PET using both a Centiloid‐like or joint propagation model approach. Additional data and consideration of the advantages and disadvantages of each will be needed to recommend one approach over the other.

Estimating the time between amyloid and tau‐PET positivity: Implications for Alzheimer’s disease prevention trials

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a preclinical stage in which abnormal accumulation of amyloid‐β (Aβ) leads to phosphorylated tau aggregation. This sequence of events represents the transition between “AD pathologic change” (A+T‐) to the much riskier full AD neuropathology (A+T+, Jack et al. Alzheimers Dement. 2018). Thus, to understand the clinical relevance of the A+T‐ stage in the long term, it is important to understand the temporal course of Aβ and tau. In this study, we used longitudinal Aβ‐ and tau‐positron emission tomography (PET) to estimate the expected time gap between Aβ‐ and tau‐PET positivity, and explored factors that influenced this gap.MethodWe estimated the natural history of amyloid accumulation in AD using longitudinal Aβ‐PET data from 1690 AD‐continuum subjects from the ADNI. Specifically, we fitted a non‐linear mixed effects model (3‐knot spline) and modelled the subject‐specific “age of Aβ positivity” as random effects (Figure 1). An interval‐censored time‐to‐event analysis using “time to amyloid positivity” as time variable was performed on 318 Aβ+ ADNI participants who had available tau‐PET ([18F]flortaucipir) visual reads. Cox proportional hazards regression was used to assess whether age of onset of amyloid positivity, sex, APOE status, and cognitive impairment at follow‐up influenced the onset of tau‐PET positivity relative to Aβ‐positivity.ResultAfter ∼11 years from Aβ positivity, 50% of the CU individuals progressed to tau‐PET positivity, while only ∼17% remained tau‐PET negative after 20 years (Figure 2). Among the studied factors, only the presence of cognitive impairment accelerated the onset of visual tau‐PET positivity (HR = 2.52, p<0.001, median tau‐free survival difference ∼6 years) (Figure 3). Both female sex (HR = 1.44, p = 0.16, median tau‐free survival difference∼2.5 years) and presence of the APOE‐ε4 allele (HR = 1.44, p = 0.15, median tau‐free survival difference∼2.5 years) were trend‐level associated to faster onset of tau‐PET positivity.ConclusionThe time gap between Aβ‐ and tau‐PET positivity typically spans a decade and is highly variable across individuals. This long gap implies that a significant fraction of A+T‐ CU older individuals will never develop tau‐PET positivity and subsequent symptoms in their lifespan, which suggests that these subjects may not benefit from current disease‐modifying therapies for AD.

The role of cerebrovascular pathology in the association between amyloid‐β and tau in cognitively unimpaired and impaired individuals

AbstractBackgroundAlthough cerebrovascular pathology often co‐exists with Alzheimer’s disease pathology, it remains incompletely understood to what extent it can contribute to the progression of Alzheimer’s disease pathology. We investigated whether cerebrovascular pathology (white matter lesions [WML] and microbleeds) modified the association between amyloid‐β (Aβ) and both cross‐sectional and longitudinal tau in cognitively unimpaired (CU) and cognitively impaired (CI) individuals.MethodWe included 1240 participants from the Swedish BioFINDER‐2 cohort including 402 Aβ‐negative CU, 147 Aβ‐positive CU, 257 Aβ‐negative CI (MCI and non‐AD dementia) and 434 Aβ‐positive CI participants (MCI and AD dementia) (Table 1). All underwent baseline [18F]RO948 (tau)‐PET, and a subset (n = 678) underwent longitudinal tau‐PET (2.6±1.0‐years). We extracted tau‐PET SUVr in a temporal meta‐region‐of‐interest. For Aβ, we used global [18F]flutemetamol‐PET SUVr for CU and Aβ‐status (+/‐) for CI participants. Global WML volume was calculated using the SPM lesion segmentation tool, corrected for intra‐cranial volume and log‐transformed. Presence of microbleeds was dichotomized into absent or present (≥1) by visual read. Primary analyses included age‐, sex‐ and APOE ε4‐corrected linear mixed models between tau‐PET (outcome) and interactions between time, Aβ and WML volume/microbleeds (predictors).ResultUpon correcting for age, sex and ε4‐carriership, Aβ‐positive CU and CI participants showed significantly more microbleeds compared to Aβ‐negative participants of the same cognitive stage (both p<0.05), but no differences in WML volume was observed (both p>0.05). In CU, we observed a significant interaction effect between ≥1 microbleed and higher Aβ‐load with both greater cross‐sectional tau (β = 0.67 [CI: 0.45‐0.89], p<0.001) and longitudinal tau (β = 0.11 [CI: 0.07‐0.16], p<0.001) (Fig‐1, Table‐2). In CU, we also observed a significant interaction effect between larger WML volumes and higher Aβ‐load with greater cross‐sectional tau (β = 0.14 [CI: 0.06‐0.22], p = 0.001). When including both microbleeds and WML volume in the same model, only effects of microbleeds remained significant (Table‐2). No significant effects were observed in CI participants.ConclusionIn CU (but not CI) individuals, cerebrovascular pathology may modify the association between Aβ and tau by accelerating tau accumulation in the presence of Aβ. These results might suggest an early effect of cerebrovascular pathology on the interplay between Aβ and tau.

Potentially modifiable factors explaining monozygotic twin discordance in amyloid pathology

AbstractBackgroundThe heritability of global amyloid burden in older adults was previously found to be moderate (41%), suggesting environmental factors to play an important role in early Alzheimer’s disease (AD) pathology. Identifying these factors may aid in the development of successful prevention strategies. Several, potentially modifiable, risk factors for dementia have been previously reported by Livingston and colleagues (Lancet, 2020). We here aim to identify which of these risk factors explain observed twin discordance in amyloid pathology in a sample of cognitively unimpaired monozygotic twin‐pairs.MethodsWe included 31 initially cognitively unimpaired twin‐pairs aged>60 years from the EMIF‐AD PreclinAD study who were discordant on amyloid status (defined by visual read of dynamic [18F]flutemetamol‐PET images). Paired samples t‐tests (continuous measures) and McNemar’s tests (dichotomous measures) were applied to investigate which factors associated with twin discordance. Selected risk factors included comorbid diseases, lifestyle and vascular risk factors (see table 2).ResultsTwins were on average 72.7±7.0 years old, consisted of 48% females, and 58% Apoe‐ε4 carriers (table 1). Twins with a positive amyloid status showed lower body mass index (BMI) and glucose levels compared to their amyloid negative co‐twin (table 2, figure 1A&B). We also observed a trend towards lower diastolic blood pressure in amyloid positive twins (table 2). In accordance with inclusion criteria for the study we observed very low prevalence of comorbid disorders in both groups. Further, no group differences were observed in lifestyle factors, such as smoking, alcohol use, physical activity and sleep quality.ConclusionsIn a sample of monozygotic twin‐pairs discordant for amyloid pathology, we found lower BMI and glucose levels to be associated with the presence of amyloid pathology. Although Livingston and colleagues reported high BMI (obesity) at mid‐life (age 45‐65) to increase the risk for dementia, effects of BMI have previously been found to differ in mid‐ and late‐age populations. In line with our results, lower BMI at later life (>65 years) has previously been found to increase AD‐risk. For the development of prevention strategies, it would be of relevance to further investigate these dynamic age‐related effects.

Amyloid‐, tau‐, and FDG‐PET in amyloid‐negative patients clinically diagnosed with early‐onset Alzheimer’s disease in the LEADS study

AbstractBackgroundNegative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.MethodsWe identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.ResultsCompared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).ConclusionsAmyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes.

Amyloid‐PET, tau‐PET, and their association in sporadic early‐onset Alzheimer’s Disease: Cross‐sectional and longitudinal data from the LEADS study

AbstractBackgroundWe aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures.MethodsIn December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts.ResultsOut of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p<.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p<0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p<0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s<0.16, p’s>0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p<0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013).ConclusionIn patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.

Amyloid‐, tau‐, and FDG‐PET in amyloid‐negative patients clinically diagnosed with early‐onset Alzheimer’s disease in the LEADS study

AbstractBackgroundNegative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.MethodWe identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.ResultCompared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).ConclusionAmyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes. ”

Clinical Manifestations.

Neurodegenerative pathologies, including tau depositions, have been implicated in late-onset depression (LOD), while there is a lack of in-vivo evidence for the neuropathological basis of late-onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F-florzolotau, a radioligand for Alzheimer's disease (AD) and non-AD tau fibrils. We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty-one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age-matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F-florzolotau and 11C-PiB, respectively. Amyloid positivity was determined by a visual read of 11C-PiB-PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z-score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z-score ≥ 2.0. 18F-florzolotau-PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C-PiB-PET-positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C-PiB-PET-positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C-PiB-negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations. Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non-AD tauopathies indicative of distinct early-stage frontotemporal lobar degeneration subcategories.

The association between AD biomarkers and neuropsychiatric symptoms in subjective cognitive decline; the SCIENCe project

AbstractBackgroundNeuropsychiatric symptoms (NPS) are increasingly recognized as non‐cognitive manifestation of Alzheimer’s disease (AD). However, the relationship between AD‐related pathology and NPS remains unclear. We aimed to investigate the cross‐sectional association between Alzheimer biomarkers and neuropsychiatric symptoms (NPS) in individuals with subjective cognitive decline (SCD) presenting at a memory clinic. In addition, we evaluated personality traits and education as potentially modifying factors of this association.MethodWe included 346 individuals with SCD (age: 62.9±7.8) from the SCIENCe cohort, including 92 amyloid positive participants (age: 66.4±7.0, Female: 44.6%, MMSE: 28.5±1.3) and 254 amyloid negative participants (age: 61.6±7.7, Female: 40.6%, MMSE: 28.6±1.3). Amyloid status was determined by amyloid PET or CSF biomarkers according to visual read or established cut points. Neuropsychiatric symptoms were assessed using the Geriatric Depression Scale (GDS; n = 282), the Center for Epidemiological Studies‐Depression (CES‐D; n = 225), the Hospital Anxiety and Depression Scale – anxiety subscale (HADS‐A; n = 225) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q; n = 198). We used linear regression analyses, adjusted for age and sex, to assess the association between amyloid status and NPS. In secondary analyses, we tested for interactions between amyloid status and (1) neuroticism (Dutch Personality Questionnaire), (2) somatization, (Four‐Dimensional Symptom Questionnaire), and (3) educational level (Dutch Verhage scale).ResultAmyloid status was not associated with GDS, CES‐D, HADS‐A and NPI‐Q scores in univariable analyses. When we evaluated effect modification, we found an interaction between amyloid status and neuroticism in the association with NPI‐Q (p<0.05), indicating a positive association between amyloid status and NPS in participants with a low level of neuroticism (β: 2.56±2.24), and a negative association in participants with a high level of neuroticism (β: ‐4.09±3.23).ConclusionIn this cross‐sectional analysis in individuals with SCD, amyloid status was hardly associated with neuropsychiatric symptoms. In future studies, we focus on amyloid status as determinant of change in NPS over time.

Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population

BackgroundPrevious studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique.MethodsWe analyzed longitudinal data from 200 patients (Mage = 61.8, 45.5% female, MMMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1–9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00–7.02). VR − and VR + patients were compared on mortality rates with Cox Hazard’s model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2–6.3).ResultsAt baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR − group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR − and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR − cases (VR − = 14/35, 40% vs VR + = 2/73, 2.7%, χ2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR − patients based on MMSE (β = − 1.17, p = 0.004), episodic memory (β = − 0.78, p = 0.003), fluency (β = − 1.44, p < 0.001), and attention scores (β = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR − and showed limited amyloid pathology.ConclusionIn a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.

Visual acuity and reading print size requirements in children with vision impairment

ABSTRACT Clinical Relevance The support of students with a vision impairment throughout education could be enhanced by assessing the functional reading ability of the individual. This visual assessment could inform educators of individualised student needs and potentially improve the academic achievement for these students. Background Support for children with a vision impairment within a classroom is typically based on clinical findings of distance visual acuity and visual fields. Therefore, determining optimal print size for reading is essential to ensure best academic outcomes. Secondary aims were to investigate the possible impact of underlying pathology on reading ability. Methods Forty-seven participants were recruited from a state-wide support service for children with a vision impairment in South Australia. Three visual acuity groups were formed based on World Health Organisation definitions of mild, moderate, and severe vision impairment. Correlation between clinical measures of distance visual acuity using the Freiburg Visual Acuity Test, were compared with reading acuity and critical print size (smallest font before reading speed reduced) using Minnesota low vision reading chart (MNREAD). Results No significant correlations were found for mild (0.20–0.49 logMAR) and severe (1.00–1.52 logMAR) vision impairment groups between distance visual acuity and reading acuity read (p = .64, CI [−.585, .395]/p = .82, CI [−.48, .58]) or critical print size (p = .78, CI [−.57, .45]/p = .43, CI [−.34, .68]. A significant correlation was found for the moderate vision impairment group: 0.50–0.99 logMAR for minimum reading acuity (p < .001, CI [.44, .91]) and critical print size (p = .03, CI [.05, .80]). Conclusions Standard clinical measures of distance visual acuity are an unpredictable estimate of reading ability in children with mild and severe vision impairment. Additional measures of functional near reading ability could provide a more meaningful indicator of reading ability and help provide optimum support to students through education.

44 Can Clinical Trial data Inform our Understanding of the role of Depressive Symptoms in Alzheimer's Disease?

Objective:Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).Participants and Methods:The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of &gt; 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.Results:Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).Conclusions:These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies.

Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = -0.52, CI -0.74 to -0.30, p < 0.001) and participants with AD (β = -0.30, CI -0.58 to -0.02, p = 0.04). The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline.

JS09.5.A18F-FLUCICLOVINE PET FOR DETECTION OF RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY: IMAGE INTERPRETATION CRITERIA RESULTS FROM PURSUE, A PROSPECTIVE PHASE 2 TRIAL

Abstract BACKGROUND Differentiating radiation necrosis from tumour progression after radiation therapy (RT) for brain metastases (BM) remains clinically challenging, and accurate imaging is crucial to prevent unnecessary surgery or unwarranted changes in therapy. 18F-Fluciclovine is a PET radiopharmaceutical with low background uptake in the brain and increased uptake in BM. The PURSUE study (NCT04410367) aimed to establish image interpretation criteria (IIC) for detecting suspected recurrent BM after RT using 18F-fluciclovine PET, based on several measures of lesion uptake. MATERIAL AND METHODS Across 7 US sites, 23 patients with solid tumour BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine PET (185 MBq) &amp;lt;42 days post-MRI and 1-21 days pre-craniotomy. Three independent, blinded readers qualitatively rated lesion 18F-fluciclovine uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland). The primary endpoint was the diagnostic performance of different thresholds of lesion uptake on qualitative (visual) reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]), and dynamic measures. A committee, including two independent imaging physicians, reviewed all data to establish the IIC, which were subsequently used to evaluate the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions underwent histopathological analysis, with 10 (43%) being pathologically confirmed BM recurrence. The highest performing qualitative measure of 18F-fluciclovine lesion uptake was ‘marked’, rendering 92-100% and variable (40-80%) across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, the committee established IIC as: "Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely." Application of these IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% positive predictive value, and 83-85% negative predictive value across readers. CONCLUSION PURSUE is the first prospective, multicentre study to define IIC for 18F-fluciclovine PET for accurate identification of suspected recurrent BM after RT, verified by histopathology. In this initial cohort, the IIC convey excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine PET in future studies. This study was sponsored by Blue Earth Diagnostics Ltd.

Automatic covariance pattern analysis outperforms visual reading of 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in variant progressive supranuclear palsy.

To date, studies on positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Capillary flow-driven immunoassay platform for COVID-19 antigen diagnostics

Over the last few years, the SARS-CoV-2 pandemic has made the need for rapid, affordable diagnostics more compelling than ever. While traditional laboratory diagnostics like PCR and well-plate ELISA are sensitive and specific, they can be costly and take hours to complete. Diagnostic tests that can be used at the point-of-care or at home, like lateral flow assays (LFAs) are a simple, rapid alternative, but many commercially available LFAs have been criticized for their lack of sensitivity compared to laboratory methods like well-plate ELISAs. The Capillary-Driven Immunoassay (CaDI) device described in this work uses microfluidic channels and capillary action to passively automate the steps of a traditional well-plate ELISA for visual read out. This work builds on prior capillary-flow devices by further simplifying operation and use of colorimetric detection. Upon adding sample, an enzyme-conjugated secondary antibody, wash steps, and substrate are sequentially delivered to test and control lines on a nitrocellulose strip generating a colorimetric response. The end user can visually detect SARS-CoV-2 antigen in 15–20 min by naked eye, or results can be quantified using a smartphone and software such as ImageJ. An analytical detection limit of 83 PFU/mL for SARS-CoV-2 was determined for virus in buffer, and 222 PFU/mL for virus spiked into nasal swabs using image analysis, similar to the LODs determined by traditional well-plate ELISA. Additionally, a visual detection limit of 100 PFU/mL was determined in contrived nasal swab samples by polling 20 untrained end-users. While the CaDI device was used for detecting clinically relevant levels of SARS-CoV-2 in this study, the CaDI device can be easily adapted to other immunoassay applications by changing the reagents and antibodies.

Efficacy of LAMP assay for Mycobacterial spp. detection to prevent treatment delays and onset of drug resistance: a systematic review and meta-analysis.

Tuberculosis (TB) remains a deadly disease affecting one-third population globally. Long turnaround time and poor sensitivity of the conventional diagnostics are the major impediments for faster diagnosis of Mycobacterial spp to prevent drug resistance. To overcome these issues, molecular diagnostics have been developed. They offer enhanced sensitivity but require sophisticated infrastructure, skilled manpower and remain expensive. In that context, loop-mediated isothermal amplification (LAMP) assay, recommended by the WHO in 2016 for TB diagnosis, sounds as a promising alternative that facilitates visual read outs. Therefore, the aim of the present study is to conduct a meta-analysis to assess the diagnostic efficiency of LAMP for the detection of a panel of Mycobacterium spp. following PRISMA guidelines using scientific databases. From 1600 studies reported on the diagnosis of Mycobacterium spp., a selection of 30 articles were identified as eligible to meet the criteria of LAMP based diagnosis. It was found that most of the studies were conducted in high disease burden nations such as India, Thailand, and Japan with sputum as the most common specimen to be used for LAMP assay. Furthermore, IS6110 gene and fluorescence-based detections ranked as the most used target and method respectively. The accuracy and precision rates mostly varied between 79.2% to 99.3% and 73.9% to 100%, respectively. Lastly, a quality assessment based on QUADAS-2 of bias and applicability was conducted. LAMP technology could be considered as a feasible alternative to current diagnostics considering high burden for rapid testing in low resource regions.

Evaluating the diagnostic performance of 18F-fluciclovine for detection of recurrent brain metastases after radiation therapy: Results from a prospective phase 2 trial.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place &lt;42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

Increased cerebral blood flow is associated with higher baseline amyloid burden in a cognitively unimpaired population

AbstractBackgroundAs cerebrovascular and Alzheimer’s proteinopathy have previously shown to affect cerebral blood flow (CBF) as well as cognition, CBF could be a potential early hemodynamic biomarker of cognitive decline. Here, we investigated to what extent cardiovascular risk factors and amyloid burden affect CBF in an elderly cognitively unimpaired (CU) population.MethodWe included 153 CU participants (minimal MMSE = 28) from the EMIF‐AD PreclinAD Twin60++ cohort (Table 1), who underwent [18F]flutemetamol PET and arterial spin labeling (ASL) MRI. Amyloid‐PET scans were visually assessed as negative or positive, upon which participants were grouped based on their longitudinal changes in amyloid positivity (visual read groups). Cortical amyloid burden was quantified with the Centiloid method globally and for 4 early amyloid accumulation regions of interest (ROIs). ASL scans were processed and quantified with ExploreASL for total gray matter (GM), and for vascular territories overlapping with the amyloid ROIs (Figure 1). Longitudinal analysis including baseline Centiloid values and yearly CBF change rates (Delta CBF) was performed for 98 participants with longitudinal imaging data available (4.23 years ± 0.43 follow‐up time). Associations between CBF and amyloid — with and without the interaction of vascular risk factors (i.e., Framingham score) — were assessed using generalized estimating equations (GEEs), both for baseline and rates of change measurements. Models were adjusted for age, sex, and twin dependency.ResultWhile no association between amyloid burden and CBF was observed across the cohort, in participants with a high Framingham vascular risk score, higher amyloid was associated with increased CBF, for most ROIs (Table 2, Figure 2). Additionally, precuneus amyloid burden was predictive of CBF change in the corresponding vascular territory (Figure 3). Visual reading shows that subjects with high amyloid burden at baseline had a higher increase of CBF at follow‐up (Stable AB+, Figure 4).ConclusionWe found that the combination of cardiovascular risk and amyloid burden in AD signature regions was associated with increased CBF in CU individuals, which may reflect a vascular or inflammatory compensatory response to early Alzheimer pathology. Future studies may help understanding how these mechanisms affect cognition.