Global Standardized Uptake Value Ratio Research Articles

Evaluation of ComBat harmonization for reducing across-tracer differences in regional amyloid PET analyses.

Introduction Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [18F]-florbetapir (FBP) and [11C]-Pittsburgh Compound-B (PiB). Methods One-hundred-thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within ninety days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified. Results In the head-to-head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP-to-PiB proportions. Conclusion ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses.

Novel β-amyloid PET Imaging Study of [18F]92 in Patients with Cognitive Decline.

[18F]-4-((E)-(((E)-4-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)benzylidene)-hydrazono)methyl)-N-methylaniline ([18F]92) is a novel positron emission tomography (PET) tracer previously reported to exhibit high binding affinity to aggregated β-amyloid (Aβ). This study aims to report a fully automated radiosynthesis procedure for [18F]92, explore its radioactive distribution in the brains of healthy subjects, and investigate its potential application value in the early diagnosis of Alzheimer's disease (AD). The fully automated radiosynthesis of [18F]92 was performed on the AllinOne module. Thirty one participants were recruited for this study. Dynamic [18F]92 PET imaging was conducted over 0-90 min period to assess time-activity curves (TAC) and standardized uptake value ratio (SUVR) curves in cognitively normal (CN) subjects. All participants were visually classified as either positive (+) or negative (-). Semiquantitative analyses of [18F]92 were performed by calculating SUVRs in different regions of interest. Furthermore, the study analyzed the relationships between global SUVR and plasma AD biomarkers, including Aβ42, Aβ40, P-tau181, and T-tau. The automated radiosynthesis of [18F]92 was completed within 50 min, yielding a radiochemical purity of greater than 95% and a radiochemical yield of 36 ± 3% (nondecay-corrected). Among the participants, 15 were estimated as Aβ (-) and 16 as Aβ (+). TACs indicated that [18F]92 rapidly crossed the blood-brain barrier within 10 min, followed by a rapid decrease, which then slowed down in the last 50-90 min. SUVR curves revealed that SUVR values stabilized around 60-70 min after injection and reached an equilibrium between 70 and 90 min, primarily in the cerebral cortex. SUVRs of Aβ (+) participants were significantly higher than those of Aβ (-) individuals within the cerebral cortex. In addition, Aβ42 and the Aβ42/Aβ40 ratio exhibited negative correlations with global SUVR, while plasma P-tau181 and the P-tau181/T-tau ratio displayed positive correlations with global SUVR. [18F]92 exhibits excellent pharmacokinetic properties in the human brain and can be synthesized automatically on a large scale. [18F]92 is a promising and reliable radiotracer for estimating Aβ pathology accumulation, providing valuable assistance in AD diagnosis and guiding clinical trials of therapeutic drugs.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer’s disease from cognitively unimpaired amyloid-positive individuals

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer’s disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Alterations in Gut Microbiota and Their Correlation with Brain Beta-Amyloid Burden Measured by 18F-Florbetaben PET in Mild Cognitive Impairment Due to Alzheimer's Disease.

(1) Background: This study investigated changes in the gut microbial composition of individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and their relationship with positron emission tomography (PET) amyloid accumulation. (2) Methods: In total, 17 cognitively normal individuals without amyloid-beta (Aβ) accumulation (Aβ-NC) and 24 with Aβ-positive mild cognitive impairment (Aβ+MCI) who underwent 18F-florbetaben PET and fecal bacterial 16S ribosomal RNA gene sequencing were enrolled. The taxonomic compositions of the Aβ-NC and Aβ+MCI groups were compared. The abundance of taxa was correlated with the standardized uptake value ratio (SUVR), using generalized linear models. (3) Results: There were significant differences in microbiome richness (ACE, p = 0.034 and Chao1, p = 0.024), alpha diversity (Shannon, p = 0.039), and beta diversity (Bray-Curtis, p = 0.018 and Generalized UniFrac, p = 0.034) between the Aβ-NC and Aβ+MCI groups. The global SUVR was positively correlated with the genus Intestinibacter (q = 0.006) and negatively correlated with the genera Roseburia (q = 0.008) and Agathobaculum (q = 0.029). (4) Conclusions: In this study, we identified significant changes in the gut microbiota composition that occur in individuals with MCI due to AD. In particular, the correlation analysis results between PET amyloid burden and gut microbial abundance showed that amyloid deposition is associated with a reduction in specific taxa involved in butyrate production.

Relationship Between Amyloid Positivity and Sleep Characteristics in the Elderly With Subjective Cognitive Decline.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognition and performance of daily activities. Recent studies have attempted to establish the relationship between AD and sleep. It is believed that patients with AD pathology show altered sleep characteristics years before clinical symptoms appear. This study evaluated the differences in sleep characteristics between cognitively asymptomatic patients with and without some amyloid burden. Sleep characteristics of 76 subjects aged 60 years or older who were diagnosed with subjective cognitive decline (SCD) but not mild cognitive impairment (MCI) or AD were measured using Fitbit® Alta HR, a wristwatch-shaped wearable device. Amyloid deposition was evaluated using brain amyloid plaque load (BAPL) and global standardized uptake value ratio (SUVR) from fluorine-18 florbetaben positron emission tomography. Each component of measured sleep characteristics was analyzed for statistically significant differences between the amyloid-positive group and the amyloid-negative group. Of the 76 subjects included in this study, 49 (64.5%) were female. The average age of the subjects was 70.72±6.09 years when the study started. 15 subjects were classified as amyloid-positive based on BAPL. The average global SUVR was 1.598±0.263 in the amyloid-positive group and 1.187±0.100 in the amyloid-negative group. Time spent in slow-wave sleep (SWS) was significantly lower in the amyloid-positive group (39.4±13.1 minutes) than in the amyloid-negative group (49.5±13.1 minutes) (p=0.009). This study showed that SWS is different between the elderly SCD population with and without amyloid positivity. How SWS affects AD pathology requires further research.

Subjective cognitive impairment score associate with regional amyloid burden and brain atrophy in subjective cognitive decline subjects

AbstractBackgroundSubjective cognitive decline (SCD) is now regarded as the first preclinical stage of Alzheimer’s disease (AD) spectrum disorders. It is important to predict which patients would progress to dementia, and screening tools might be helpful. In this study, we aimed to investigate the possible correlations between AD biomarkers‐regional amyloid burden and volume changes‐and Korean Dementia Screening Questionnaire‐Cognition (KDSQ‐C) score in SCD.MethodThis study analyzed SCD data from prospective population cohort study from July 2018 to December 2020. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid Positron Emission Tomography (PET) were performed. Demographics, physical data, social and physiological functions were also obtained.KDSQ‐C was administered to SCD subjects as part of the clinical evaluation at the 36 month follow‐up visit. KDSQ‐C included 15 questions that assess 3 dimensions: memory impairment (items 1‐5), other cognitive impairments including language impairments (items 6‐10), and the ability to perform complex tasks in daily life (items 11‐15).ResultPrevalence of subjective cognitive impairment (KDSQ‐C ≧6) among 86 subjects was 73.3%.. No significant difference was observed between groups in terms of demographic characteristics including age, sex and APOE Ɛ4 status and neuropsychological test. However, regional SUVR (amygdala, inferior temporal gyrus and precuneus) and global SUVR were significantly higher in subjectively cognitive impaired group(p&lt;0.05). There were no brain volume differences between groups.For volumetry and KDSQ‐C correlation analysis, partial correlation analysis controlled for age, sex and APOE Ɛ4 status showed significant negative correlation between left entorhinal cortex, right hippocampal volume and KDSQ‐C (r = ‐0.230, p = 0.046; r = ‐0.226, p = 0.049). Similar association was also found between KDSQ‐C memory domain score and brain volume.ConclusionKDSQ‐C can be a useful tool for screening SCD patients at a higher risk with higher amyloid deposition and brain atrophy.This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530

Race, inflammation, and amyloid deposition in Black/African American and Non‐Hispanic White older adults

AbstractBackgroundBlack/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer’s Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination.MethodOne hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group.ResultParticipants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p’s&lt;.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p&lt;.05).Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p = .029). No differences by racialized group were observed for IL6.PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = &lt;.001). Global Ab SUVr was higher in NHW than AA participants (p&lt;.05).ConclusionThe results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed.

Amyloid and Tau PET Positivity in Progressive Apraxia of Speech and Agrammatic Aphasia

AbstractBackgroundThe spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.Methods65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.ResultsThere was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).ConclusionsAβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.

Plasma oligomer βeta‐amyloid and white matter microstructural integrity in cognitively normal older adults according to cerebral amyloid deposition

AbstractBackgroundMultimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level, which is associated with earlier pathology of Alzheimer’s disease (AD). Previous studies showed that plasma levels of MDS‐OAβ were higher in patients with dementia due to AD than in cognitive normal older adults (CN), and they correlated well with conventional AD biomarkers including standardized uptake value ratio (SUVR) of Pittsburgh compound B (PiB) and CSF level of Aβ42, p‐Tau, and t‐Tau. However, no previous study investigated MDS‐OAβ difference in CN with or without cerebral Aβ burden. In addition, associations among MDS‐OAß, cerebral Aß deposition, aberrance of white matter integrity, and cortical thickness in CN is not elucidated.MethodWe studied 34 CN with amyloid‐PET negative and 23 CN with amyloid‐PET positive results who received MDS‐OAβ, structural MRI, and diffusion tensor imaging (DTI).ResultAmyloid‐PET positive group showed higher MDS‐OAß level than amyloid‐PET negative group, but two groups did not differ in WM integrity or cortical thickness. MDS‐OAβ level was significantly higher in amyloid‐PET positive group than in amyloid‐PET negative group. MDS‐OAβ positive group had significantly higher cerebral AB deposition, or mean global SUVR values, than MDS‐OAβ negative group. There was a positive correlation between MDS‐OAβ level and PET‐SUVR. In terms of DTI analysis, MDS‐OAβ positive group had significantly lower FA in the left forceps minor of corpus callosum and right superior longitudinal fasciculus than in lower MDS‐OAβ negative group. In addition, the FA values were negatively correlated with MDS‐OAβ level (figure 1). MDS‐OAB positive group showed a significant reduction in the cortical thickness in the left fusiform when compared with the MDS‐OAB negative groupConclusionPlasma MDS‐OAβ value might reflect cerebral amyloid status and global cerebral Aß retention in CN. We elucidated toxic role of OAβ by showing that the plasma OAβ value were associated with decrement of WM microstructural integrity in the early pathological process of AD. Cortical thickness did not differ according to cerebral Aβ burden but rather was associated with higher plasma OAβ level. Thus, MDS‐OAβ value might reflect earlier, and different, pathology than cerebral Aß retention measured using amyloid PET scan in CN with AD continuum.

Distinct associations between tau PET and cognitive impairment across brain regions and cognitive domains in Alzheimer’s disease

AbstractBackgroundCompared with biofluid‐biomarkers, tau‐PET shows stronger association with cognitive impairment (Ossenkoppele,R‐2021) and decline, and better detects Alzheimer’s disease (AD) pathology (Coomans,EM‐2022; Smith,R‐2022). Conventionally, tau‐cognition relationship has been evaluated between global cortical tau‐PET and composite cognitive scores. However, tau‐PET binding patterns are heterogenous, with regional binding showing strong correlations with domain‐specific cognitive performance and decline. The goal of this study was to evaluate domain‐specific patterns of tau‐PET at baseline and in change‐from‐baseline (CFB) in symptomatic AD patients.MethodAmyloid‐positive participants (n = 172) with a clinical diagnosis of mild‐cognitive‐impairment (n = 97) or dementia due to AD (n = 76) and amyloid‐negative healthy‐controls (n = 68) underwent a 18Flortaucipir tau‐PET and neuropsychological testing (AV1451‐A05:NCT02016560) at baseline and 18months. Observed cognitive scores in impaired patients were normalized to age‐adjusted outcomes in healthy‐controls at baseline and 18months (Ossenkoppele,R‐2015). These scores were subsequently averaged within the episodic‐memory, semantic‐memory, language, visuospatial, and executive function cognitive domains (Malpetti,M‐2022). Standardized uptake value ratio (SUVr) in automated‐anatomical‐labelling regions (Tzourio‐Mazoyer,M‐2002) and AD‐specific region (MUBADA; Devous,M‐2017) was calculated in reference to cerebellum‐crus. The CFB (18months‐baseline) in SUVr and domain‐specific sub‐scores were calculated for all participants. Correlations between global SUVr versus composite cognitive score and regional SUVr versus domain‐specific scores at baseline and CFB were calculated.ResultDifferential cross‐sectional tau‐PET patterns showed significant negative associations with domain‐specific cognitive performance (Fig.1A). When evaluated longitudinally, higher global CFB in tau‐PET SUVr showed no‐to‐modest correlation with cognitive decline (Fig.2: ADAS‐Cog11 = 0.012, FAQ = ‐0.015, MMSE = ‐0.210, CDR‐SB = 0.014), however, heterogeneous associations were observed at the regional‐ and voxel‐level (Fig.1B,Fig.3), ranging from maximum of r = ‐0.45 (p&lt;0.001; frontal‐inferior and visuospatial) to minimum of r = ‐0.002 (p&lt;0.1; lingual and episodic). Increase in tau‐PET signal was associated with greater cognitive decline (i.e. visuospatial function: predominantly frontal; executive function: parietal and prefrontal; semantic‐memory: superior temporal region). An extensive and asymmetric tau‐PET pattern (L&gt;R) in frontal and occipital regions was related to language.ConclusionWe found associations between patterns of tau accumulation and domain‐specific cognitive decline in MCI and AD dementia. After validations using larger datasets, these relationships can supplement widely used associations between global tau‐PET and composite cognitive scores and, therefore, enhance tau PET‐guided and patient‐centered staging, prognosis, and response assessment.

Sex-Related Disparities in the Resting State Functional Connectivity of the Locus Coeruelus and Salience Network in Preclinical Alzheimer's Disease.

Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer's disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition.

Impacts of baseline biomarkers on cognitive trajectories in subjective cognitive decline: the CoSCo prospective cohort study

BackgroundSubjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease (AD); however, the rates of cognitive decline are variable according to underlying pathologies and biomarker status. We conducted an observational study and aimed to investigate baseline characteristics and biomarkers related with cognitive declines in SCD. Our study also assessed whether SCD participants showed different cognitive and biomarker trajectories according to baseline amyloid deposition.MethodsThis study is a part of a longitudinal cohort study conducted in multi-centers in South Korea between 2018 and 2021. Individuals (≥ 60 years old) with persistent cognitive complaint despite of normal cognitive functions were eligible for the study. All participants underwent neuropsychological tests, florbetaben PET scans, plasma amyloid markers, and brain MRI scans. Annual follow-up evaluations included neuropsychological tests and assessments for clinical progressions. Regional brain volumetry and amyloid burden represented by PET-based standardized uptake value ratio (SUVR) were measured. We compared cognitive and brain atrophic changes over 24 months between amyloid positive-SCD (Aβ + SCD) and amyloid negative-SCD (Aβ-SCD) groups. Baseline factors associated with cognitive outcomes were investigated.ResultsA total of 120 participants with SCD were enrolled and 107 completed follow-up evaluations. Aβ + SCD participants (n = 20, 18.5%) were older and more frequently APOE4 carriers compared with Aβ-SCD participants (n = 87). Baseline cognitive scores were not different between the two groups, except the Seoul Verbal Learning Test (SVLT) scores showing lower scores in the Aβ + SCD group. After 24 months, plasma amyloid markers were higher, and regional volumes (entorhinal, hippocampal, and pallidum) were smaller in the Aβ + SCD participants compared with Aβ-SCD participants adjusted by age, sex, and baseline volumes. SVLT delayed recall and controlled oral word association test (COWAT) scores indicated more declines in Aβ + SCD participants. Baseline left entorhinal volumes were related to verbal memory decline, while baseline frontal volumes and global SUVR values were related to frontal functional decline.ConclusionAβ + SCD participants showed more cognitive decline and medial temporal atrophic changes during 24 months. Baseline neurodegeneration and amyloid burden were related with future cognitive trajectories in SCD.Trial registrationThis study was registered at CRIS (KCT0003397).

Quantifying AD‐related brain amyloid with linearised progression models: Model‐based vs. data‐based

AbstractBackgroundBrain amyloid‐β (Aβ) is the pathological hallmark of Alzheimer’s disease (AD). In logistic disease models, Aβ accumulation is a sigmoid function of time‐since‐disease‐onset (TSDO) (figure 1). Previous positron emission tomography (PET)‐based models vary accumulation onset(t50) and duration(r) globally; capacity(K) and baseline(NS) regionally (Whittington2018). We confirm existing approaches and propose a more powerful ICA‐based approach to quantify disease severity and estimate TSDO.MethodWe used 1071 18F‐florbetapir standard uptake value ratio (SUVR) images from the ADNI‐2 study (adni.loni.usc.edu/data‐samples/data‐types/pet). Images were mapped into MNI space. Averages were extracted using the Harvard‐Oxford brain‐atlas. Whole‐brain tracer‐specific sigmoid parameters (Jack2013) obtained from the literature were used to estimate TSDO.Of 16 models of regional Aβ accumulation (each of the 4 regional sigmoid parameters varied either regionally or globally), the optimal Bayesian information criterion was found with global t50 and r, and regional NS and K (figure 1) with global values r = 6.16y and t50 = 4.10y.Linearised maps of NS and K were obtained by regressing the SUVR maps onto the global sigmoid. We also estimated these maps as independent components, using a 2‐component ICA on the SUVR maps. Both outcomes were used to quantify Aβ accumulation from SUVR images as weighting factors of the accumulation map.We compared the weights from the logistic model and the ICA model in ADNI, using effect size measured with Hedges' g between cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (EMCI/MCI/LMCI) and AD groups. We compared 3 longitudinal visits (N = 112) in the OASIS‐3 study (see www.oasis‐brains.org) with both methods, global SUVR and Centiloid (Klunk2015) using 11C‐PiB PET SUVR images.ResultMaps of accumulation capacity from both models had spatial correlation of 0.86 (figure 2); baseline maps had spatial correlation of 0.95. Hedges' g between ADNI groups was 2.25 for K, and 2.42 for ICA (1.46 for global SUVR). In OASIS‐3, Hedges' g between visits was 1.24 for K, 1.46 for ICA (global SUVR 0.15, Centiloid 0.4).ConclusionWe demonstrate that linear accumulation models can be used to quantify brain Aβ with PET; maps obtained by ICA yield larger effect sizes than the logistic method for differentiating groups and measuring changes between visits.

Reduced cortical cholinergic innervation correlates with cognitive decline in mild cognitive impairment

AbstractBackgroundDysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. The association of cortical cholinergic denervation with diverse cognitive profiles in dementia, particularly at early stages, has not yet been fully explored. We assessed the relationship of cholinergic denervation in the cortex measured using 18F‐fluoroethoxybenzovesamicol (FEOBV) with cognitive decline at an early stage of dementia.MethodParticipants (8 with mild cognitive impairment (MCI) and 10 cognitively unimpaired (CU) controls, aged 60‐86, 55.6% female, MMSE = 28.7±1.5) underwent neuropsychological assessment and FEOBV PET imaging. The neuropsychological battery of tests included measures of memory, executive function, attention and language. Domain‐specific composite scores were calculated by averaging z‐scores of the related tests or subtasks within a domain. FEOBV images were co‐registered to the concurrent structural MRI and normalised to the supratentorial white matter reference region resulting in a standardized uptake value ratio (SUVR). Voxel‐wise analysis was performed on normalised FEOBV images to investigate associations with clinical diagnosis and domain‐specific cognitive performance. Voxel‐based morphometry was also performed to rule out differences in brain morphology. All analyses were corrected for age, sex and total intracranial volume and adjusted for multiple comparisons.ResultThe MCI group showed significantly lower global FEOBV SUVR in the cortex although only a focal cluster of reductions near the right middle temporal gyrus was found in the voxel‐wise comparisons. When associations with cognitive performance profiles were assessed in the full cohort, regional positive correlations were found between FEOBV SUVR and cognitive scores across different domains (Figure 1), although these did not include memory. For executive functioning, widespread correlation patterns were observed across both cortical and subcortical regions. Moreover, overlapping profiles were identified for all three cognitive domains of executive function, attention and language, which covered the anterior cingulate gyrus, olfactory cortex, calcarine cortex, middle temporal gyrus and caudate nucleus.ConclusionWe have demonstrated that the topographic profile of FEOBV retention correlated with reduced cognitive performance in different domains, suggesting that reduced cortical cholinergic terminal integrity is an important pathological feature of cognitive decline.

Establishing and validating unbiased cut‐offs for tau PET with Gaussian mixture model in Alzheimer’s disease

AbstractBackgroundTau PET positivity (T+) is recommended in Alzheimer’s disease (AD) trials involving preclinical and prodromal AD. As unbiased cut‐offs are still lacking, we established and validated data‐driven T+ PET cut‐offs for AD.MethodData were from ADNI (estimation cohort) and Geneva memory center (validation cohort). 18F‐Flortaucipir standardized uptake value ratios (SUVr) were computed for a global temporal meta‐ROI and for cortical regions corresponding to Braak‐based stages I‐VI in amyloid negative (Aβ−) cognitively normal (CN), Aβ+ CN, Aβ+ MCI and AD. For Tau PET data‐driven cut‐off estimation, Gaussian mixture model (GMM) was applied on the global and regional SUVr distributions in Aβ− CN and AD (n = 269). The GMM cut‐offs’ performance was compared with published 18F‐Flortaucipir cut‐offs (Mattsson et al., 2017) by assessing the percentage of T+ subjects within each diagnostic group.ResultCut‐offs were 1.36 for temporal meta‐ROI and ranged 1.20‐1.39 for stages. In the validation cohort, all Aβ− CN were tau negative (T−), while T+ percentage increased along the Aβ+ continuum (CN&lt;MCI&lt;AD) for temporal meta‐ROI (33&lt;64&lt;75) and stages I‐II (50&lt;73&lt;75), III (17&lt;55&lt;58), IV (17&lt;57&lt;75), V (0&lt;18&lt;50) and VI (0&lt;5&lt;33). Previously published cut‐offs reported a higher frequency of T+ in the AD spectrum and identified T+ subjects in the Aβ‐ CN group.ConclusionGMMs unbiased 18F‐Flortaucipir SUVr cut‐offs showed lower T+ percentage in Aβ− CN than published cut‐offs, possibly indicating lower false positive rates and suggesting that they might be useful for the in‐vivo assessment of participants eligibility in future preclinical and prodromal AD trials.

One year longitudinal change of tau accumulation on [18F]PI‐2620 PET in Alzheimer spectrum

AbstractBackgroundWe investigated longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients with Alzheimer’s disease (AD) spectrum using [18F]PI‐2620 PET.MethodWe enrolled 54 (69.9±8.5 y, M:F = 16:38) participants (8 cognitively normal [NC], 28 mild cognitive impairment [MCI], 18 AD) who completed [18F]PI‐2620 PET scans at baseline and 1 y follow up. Subject also underwent [18F]florbetaben PET (baseline only), MRI and neuropsychological tests. Aβ PET images were visually scored as positive or negative. Aβ+ MCI &amp; AD were classified into early onset (&lt;65 y, EO+) and late onset (≥65, LO+) group. Standardized uptake value ratios (SUVr) of [18F]PI‐2620 PET were determined by cerebral to inferior cerebellar ratio and corrected for partial volume effect. Cortical volumes were calculated from 3D T1‐weighted MR images. We also investigated a correlation between the progression of tau accumulation and cognitive decline.ResultThirty eight out of 57 participants showed Aβ+ (1 NC, 20 MCI, 17 AD). Global SUVr values of [18F]PI‐2620 PET were 0.96±0.07 in 7 Aβ‐ NC, 1.23±0.41 in 17 LO+ (76.7±3.8y) and 1.86±0.87 in 20 EO+ (63.4±5.4y) (p&lt;0.001). It increased by 0.09±0.14 (7.0%) in LO+ and 0.14±0.27 (11.6%) in EO+ in contrast to no change in NC‐. EO+ showed abundant tau accumulation in Braak III‐V areas at baseline with rapid accumulation in Braak V area (0.33±0.41 [13.9%] vs. 0.08±0.14 [6.7%], p = 0.010) than LO+ group. It showed abundant and rapid accumulation on Braak 3 areas in LO+ group (1.61±0.53 at baseline, change: 0.15±0.25 [8.2%]). Deterioration of the visuospatial function and verbal memory was associated with the progression of tau accumulation in Braak III‐V areas in EO+ group. Progressive atrophy in Braak III‐V areas were associated with the progression of tau accumulation in LO+ group whereas hippocampal atrophy did in EO+ group.ConclusionTau accumulation measured by [18F]PI‐2620 in EO+ showed rapid accumulation in Braak III‐V areas and correlated with deterioration of the visuospatial function and verbal memory. It suggests that [18F]PI‐2620 PET is potential biomarker for selecting therapeutic target and monitoring treatment effect for tau targeting treatment.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

Visual reading for [18F]Florzolotau ([18F]APN-1607) tau PET imaging in clinical assessment of Alzheimer's disease.

Tau-targeted positron emission tomography (tau-PET) is a potential tool for the differential diagnosis of Alzheimer's disease (AD) and to clarify the distribution of tau deposition. In addition to the quantitative analysis of tau-PET scans, visual reading supports the assessment of tau loading for clinical diagnosis. This study aimed to propose a method for visually interpreting tau-PET using the [18F] Florzolotau tracer and investigate the performance and utility of the visual reading. A total number of 46 individuals with 12 cognitively unimpaired subjects (CU), 20 AD patients with mild cognitive impairment (AD-MCI), and 14 AD with dementia (AD-D) patients with both [18F]Florbetapir amyloid PET and [18F]Florzolotau tau PET scans were included. Clinical information, cognitive assessment, and amyloid PET scan results were recorded. For visual interpretation, a modified rainbow colormap was created and a regional tau uptake scoring system was proposed to evaluate the degree of tracer uptake and its spatial distribution within five cortical regions. Each region was scored on a scale of [0, 2] as compared to the background, and that resulted in a global scale range of [0, 10]. Four readers interpreted [18F]Florzolotau PET using the visual scale. The global and regional standardized uptake value ratios (SUVr) were also calculated for analysis. The result indicates the average global visual scores were 0 ± 0 in the CU group, 3.43 ± 3.35 in the AD-MCI group, and 6.31 ± 2.97 in the AD-D group (p < 0.001). The consensus among the four observers on image scores was high with an intraclass correlation coefficient of 0.880 (95% CI: 0.767-0.936). The average global visual score was significantly associated with global SUVr (r = 0.884, p < 0.0001) and with the CDR-sum of box (r = 0.677, p < 0.0001). The visual reading method generated a visual score of [18F]Florzolotau tau-PET with good sensitivity and specificity to identify AD-D or CU individuals from the other patients. The preliminary result also showed that the global visual scores are significantly and reliably correlated with global cortical SUVr, and associated well with the clinical diagnosis and cognitive performance.

Brain Amyloid in Sporadic Young Onset Alzheimer's Disease.

Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer's disease (AD). To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher's Exact Test. Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele.

Clinical outcomes of increased focal amyloid uptake in individuals with subthreshold global amyloid levels.

Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased β-amyloid (Aβ) uptake and global Aβ status. We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach. A total of 62 (6.4%) subjects showed increased focal Aβ uptake with subthreshold global Aβ status [global (-) and focal (+) Aβ group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment (p < 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(-)F(-). Participants with widespread Aβ involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aβ involvement G(-)F(+). Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aβ uptake and global Aβ status. Thus, researchers and clinicians should pay more attention to focal increased Aβ uptake in addition to global Aβ status.