18F-florbetapir PET Research Articles

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Amyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old. This was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors. The sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline. Amyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

Multi-instance learning attention model for amyloid quantification of brain sub regions in longitudinal cognitive decline

Amyloid PET scans help in identifying the beta-amyloid deposition in different brain regions. The purpose of this study is to develop a deep learning model that can automate the task of finding amyloid deposition in different regions of the brain only by using PET scan and without the corresponding MRI scan. 2647 18F-Florbetapir PET scans are collected from Alzheimer’s Disease Neuroimaging Initiative (ADNI) from multiple centres taken over a period. A deep learning model based on multi-instance learning and attention is proposed which is trained and validated using 80% of the scans and the remaining 20% of the scans are used for testing the model. The performance of the model is validated using Mean Absolute Error (MAE) and Root Mean Squared Error (RMSE). The proposed model is further tested upon an external dataset consisting of 1413 18F-Florbetapir PET scans from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study. The proposed model achieves MAE of 0.0243 and RMSE of 0.0320 for summary Standardized Uptake Value Ratio (SUVR) based on composite reference region for ADNI test set. When tested on the A4-study dataset, the proposed model achieves MAE of 0.038 and RMSE of 0.0495 for summary SUVR based on the composite region. The results show that the proposed model provides less MAE and RMSE when compared with existing models. A graphical user interface is developed based on the proposed model where the predictions are made by selecting the files of 18F-Florbetapir PET scans.

Associations of CSF BACE1 with amyloid pathology, neurodegeneration, and cognition in Alzheimer's disease.

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD.

The associations between nutritional status and physical frailty and Alzheimer's disease plasma biomarkers in older cognitively unimpaired adults with positive of amyloid-β PET

Background & AimsIt has been revealed good nutritional status and no physical frailty, which are modifiable lifestyle factors, are linked to less cognitive decline and a lower risk of Alzheimer’s disease (AD). We aimed to investigate the associations between nutritional status and physical frailty and plasma AD biomarkers, especially the Tau-associated biomarkers in older cognitively unimpaired (CU) adults with higher β-amyloid (Aβ) burden. MethodsThe nutritional status and physical frailty were assessed via Mini-Nutritional Assessment Short-Form (MNA-SF) and Fried frailty index. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET scan as well as 18F-MK6240 PET in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the associations between nutritional status and frailty and AD biomarkers. ResultsTwo cohorts were included in our study. A total of 129 participants with Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed MNA-SF scores, normal nutritional status, Fried frailty index scores, frailty and some domains of frailty including weight loss, maximal grip strength and exhaustion were associated with plasma p-Tau-181. Furthermore, weight loss, Fried frailty index scores and frailty were associated with higher Aβ-PET standard uptake value ratio. We further performed subgroup analyses stratified by age, sex and apolipoprotein E ε4 genotype to investigate the beneficial characteristics of nutrition and frailty in the special subgroups. Validation cohort contained 38 Aβ-PET positive participants. MNA-SF scores, normal nutritional status, Fried frailty index scores and frailty were associated with Tau burden evaluated by 18F-MK6240 PET Braak-like stages. ConclusionsOur data indicates that normal nutritional status and no physical frailty may be associated with expected trend of plasma AD biomarkers, especially less Tau pathology in older CU adults with Aβ deposition. Adjusting to these characteristics of nutrition and physical frailty may help reduce the risk of AD development.

Transcranial Blood-Brain Barrier Opening in Alzheimer's Disease Patients Using a Portable Focused Ultrasound System with Real-Time 2-D Cavitation Mapping.

Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. A phase 1 clinical study with mild to moderate AD patients (N=6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18F-Florbetapir PET. BBBO was achieved in 5 out of 6 subjects with an average volume of 983±626 mm3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8±10.7 min. Cavitation dose significantly correlated with the BBBO volume (R 2>0.9, N=4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42 (R 2=0.74), Tau (R 2=0.95), and P-Tau181 (R 2=0.86), assayed in serum-derived EVs sampled 3 days after FUS (N=5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose (R 2>0.9, N=3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery.

Specific Association of Worry With Amyloid-β But Not Tau in Cognitively Unimpaired Older Adults

Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory-6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD.

Kinetic analysis of cardiac dynamic 18F-Florbetapir PET in healthy volunteers and amyloidosis patients: A pilot study

ObjectivesThis study aimed to explore the potential of full dynamic PET kinetic analysis in assessing amyloid binding and perfusion in the cardiac region using 18F-Florbetapir PET, establishing a quantitative approach in the clinical assessment of cardiac amyloidosis disease. Materials & methodsThe distribution volume ratios (DVRs) and the relative transport rate constant (R1), were estimated by a pseudo-simplified reference tissue model (pSRTM2) and pseudo-Logan plot (pLogan plot) with kidney reference for the region of interest-based and voxel-wise-based analyses. The parametric images generated using the pSRTM2 and linear regression with spatially constrained (LRSC) algorithm were then evaluated. Semi-quantitative analyses include standardized uptake value ratios at the early phase (SUVREP, 0.5–5 min) and late phase (SUVRLP, 50–60 min) were also calculated. ResultsTen participants [7 healthy controls (HC) and 3 cardiac amyloidosis (CA) subjects] underwent a 60-min dynamic 18F-Florbetapir PET scan. The DVRs estimated from pSRTM2 and Logan plot were significantly increased (HC vs CA; DVRpSRTM2: 0.95 ± 0.11 vs 2.77 ± 0.42, t’(2.13) = 7.39, P = 0.015; DVRLogan: 0.80 ± 0.12 vs 2.90 ± 0.55, t’(2.08) = 6.56, P = 0.020), and R1 were remarkably decreased in CA groups, as compared to HCs (HC vs CA; 1.08 ± 0.37 vs 0.56 ± 0.10, t’(7.63) = 3.38, P = 0.010). The SUVREP and SUVRLP were highly correlated to R1 (r = 0.97, P < 0.001) and DVR(r = 0.99, P < 0.001), respectively. The DVRs in the total myocardium region increased slightly as the size of FWHM increased and became stable at a Gaussian filter ≥6 mm. The secular equilibrium of SUVR was reached at around 50-min p.i. time. ConclusionThe DVR and R1 estimated from cardiac dynamic 18F-Florbetapir PET using pSRTM with kidney pseudo-reference tissue are suggested to quantify cardiac amyloid deposition and relative perfusion, respectively, in amyloidosis patients and healthy controls. We recommend a dual-phase scan: 0.5–5 min and 50–60 min p.i. as the appropriate time window for clinically assessing cardiac amyloidosis and perfusion measurements using 18F-Florbetapir PET.

Transcranial blood-brain barrier opening in Alzheimer's disease patients using a portable focused ultrasound system with real-time 2-D cavitation mapping.

Background : Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. Methods : A phase 1 clinical study with mild to moderate AD patients (N = 6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18F-florbetapir PET. Results : BBBO was achieved in 5 out of 6 subjects with an average volume of 983 ± 626 mm3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8 ± 10.7 min. Cavitation dose significantly correlated with the BBBO volume (R 2 > 0.9, N = 4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42 (R 2 = 0.74), Tau (R 2 = 0.95), and P-Tau181 (R 2 = 0.86), assayed in serum-derived EVs sampled 3 days after FUS (N = 5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose (R 2 > 0.9, N = 3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. Conclusion : We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery.

Neuropsychiatric symptoms in Alzheimer's continuum and their association with plasma biomarkers

BackgroundLittle is known about association between neuropsychiatric symptoms and plasma biomarkers across the entire Alzheimer's continuum. MethodsA total of 305 individuals with amyloid-β (Aβ) deposition (determined by 18F-florbetapir PET) participated in this study, including cognitively normal controls (n = 53), subjective cognitive decline (SCD, n = 75), mild cognitive impairment (MCI, n = 74), and dementia (n = 103). Plasma biomarkers (Aβ1-42, Aβ1-40, total tau [t-tau], phosphorylated tau 181 [p-tau181], and neurofilament light [NfL]), apolipoprotein E (APOE) genotyping and Neuropsychiatric Inventory Questionnaire (NPI-Q) were completed. Neuropsychiatric symptoms were classified into four subsymdromes (hyperactivity, psychosis, affective, and apathy). Logistic regression analysis was conducted to investigate relationships between neuropsychiatric symptoms and plasma biomarkers. ResultsAbout one-third of cognitively unimpaired individuals (normal controls: 34.0 %, SCD: 28.0 %) reported one or more neuropsychiatric symptoms, and more in symptomatic stages such as MCI (40.5 %) and dementia (81.0 %). Plasma NfL significantly increased in dementia group compared to SCD and healthy controls, relating to a higher risk of aberrant motor behavior, anxiety, sleep disturbance, disinhibition, and euphoria. Older age (odds ratio [OR] = 1.079, 95 % confidence interval [CI] = 1.022–1.140, p = 0.006), lower cognitive score (OR = 0.846, 95%CI = 0.791–0.905, p < 0.001) and increased plasma NfL (OR = 1.021, 95%CI = 1.00–1.042, p = 0.041) could predict psychosis. No significant differences were found in plasma Aβ1-42/Aβ1-40, t-tau or p-tau181 across all groups, and none correlated with neuropsychiatric symptoms. LimitationsThe cross-sectional design, small sample size and use of NPI-Q. ConclusionsThis study supported neuropsychiatric symptoms as early manifestations of preclinical Alzheimer's disease, and suggested plasma NfL to be a potential biomarker for detecting neuropsychiatric symptoms in Alzheimer's continuum.

6 Posterior cerebral artery-defined white matter hyperintensities are associated with object domain memory and transentorhinal volume independently of global beta-amyloid burden

Objective:White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.Participants and Methods:114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.Results:PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).Conclusions:We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

The Association of Metabolic Brain MRI, Amyloid PET, and Clinical Factors: A Study of Alzheimer's Disease and Normal Controls From the Open Access Series of Imaging Studies Dataset.

Although brain activities in Alzheimer's disease (AD) might be evaluated MRI and PET, the relationships between brain temperature (BT), the index of diffusivity along the perivascular space (ALPS index), and amyloid deposition in the cerebral cortex are still unclear. To investigate the relationship between metabolic imaging measurements and clinical information in patients with AD and normal controls (NCs). Retrospective analysis of a prospective dataset. 58 participants (78.3 ± 6.8 years; 30 female): 29 AD patients and 29 age- and sex-matched NCs from the Open Access Series of Imaging Studies dataset. 3T; T1-weighted magnetization-prepared rapid gradient-echo, diffusion tensor imaging with 64 directions, and dynamic 18 F-florbetapir PET. Imaging metrics were compared between AD and NCs. These included BT calculated by the diffusivity of the lateral ventricles, ALPS index that reflects the glymphatic system, the mean standardized uptake value ratio (SUVR) of amyloid PET in the cerebral cortex and clinical information, such as age, sex, and MMSE. Pearson's or Spearman's correlation and multiple linear regression analyses. P values <0.05 were defined as statistically significant. Significant positive correlations were found between BT and ALPS index (r = 0.44 for NCs), while significant negative correlations were found between age and ALPS index (rs = -0.43 for AD and - 0.47 for NCs). The SUVR of amyloid PET was not significantly associated with BT (P = 0.81 for AD and 0.21 for NCs) or ALPS index (P = 0.10 for AD and 0.52 for NCs). In the multiple regression analysis, age was significantly associated with BT, while age, sex, and presence of AD were significantly associated with the ALPS index. Impairment of the glymphatic system measured using MRI was associated with lower BT and aging. 3 TECHNICAL EFFICACY STAGE: 1.

Sex and APOE genotype differences in amyloid deposition and cognitive performance along the Alzheimer’s Continuum

Conflicting findings exist regarding the differences in amyloid burden and cognitive performance based on sex and apolipoprotein E (APOE) genotype. This study aimed to investigate the brain amyloid-β (Aβ) burden and cognitive performances by sex and APOE genotype in a cohort of Aβ-positron emission tomography (PET)–positive participants. Brain Aβ burden was assessed using 18F-florbetapir PET standard uptake value ratios. Cognitive performance was evaluated using standardized neuropsychological tests. In the cognitively normal participants, females had a higher Aβ burden than males in APOE ε4 noncarriers, whereas APOE ε4 carriers had a higher Aβ burden than noncarriers in males. In the cognitively impaired participants, APOE ε4 carriers were more likely to have a higher Aβ burden than noncarriers in the brain regions of the lateral parietal gyrus, frontal gyrus, and precuneus. In addition, females were more likely to have poorer language and visuospatial performance compared to males, while the APOE genotype did not significantly impact cognitive performance. These findings further elucidate the impact of sex and APOE genotype on brain Aβ burden and sex-related cognitive performance should be considered in the Alzheimer’s Continuum.

Development of software for measuring brain amyloid accumulation using 18 F-florbetapir PET and calculating global Centiloid scale and regional Z-score values.

Quantitative measures have been proposed to aid the visual interpretation of amyloid PET. Our objective was to develop and validate quantitative software that enables calculation of the Centiloid (CL) scale and Z-score for amyloid PET with 18 F-florbetapir. This software was developed as a toolbox in statistical parametric mapping 12 running on MATLAB Runtime. For each participant's amyloid PET, this software calculates the CL scale using the standard MRI-guided pipeline proposed by the Global Alzheimer's Association Interactive Network (GAAIN) and generates a Z-score map for comparison with a new amyloid-negative database constructed from 20 healthy controls. In 23 cognitively impaired patients with suspected Alzheimer's disease, Z-score values for a target cortical area from the new database were compared with those from the GAAIN database constructed from 13 healthy controls. The CL values obtained using low-dose CT of PET/CT equipment were then compared with those obtained using MRI. The CL calculation was validated with the 18 F-florbetapir dataset in the GAAIN repository. Z-score values obtained from the new database were significantly higher (mean±standard deviation, 1.05±0.77; p<.0001) than those obtained from the GAAIN database. The use of low-dose CT provided CL scales that were highly correlated with those obtained with MRI (R2 =.992) but showed a slight yet significant underestimation (-2.1±4.2; p=.013). Our quantification software provides the CL scale and Z-score for measuring overall and local amyloid accumulation with the use of MRI or low-dose CT.

Genetic Moderation of the Association of β-Amyloid With Cognition and MRI in Alzheimer Disease.

There is considerable heterogeneity in the association between increasing amyloid β (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer's disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examine an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in two large cohorts. In 2953 cognitively-unimpaired participants from the A4 study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment. In A4, four genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of three variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β =-2.29, SE=0.40, pFDR=0.02, nearest gene ARPP21; rs71567499, β =-2.16, SE=0.38, pFDR=0.02, nearest gene PPARD; rs10974405, β =-1.68, SE=0.29, pFDR=0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β =0.71, SE=0.13, pFDR=0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both A4 and ADNI. In A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β =-1.01, SE=0.21, t=-4.90, p<0.001). In ADNI, rs76366637 was associated with accelerated cognitive decline (χ2=15.3, p=0.004) and atrophy over time (χ2=26.8, p<0.001), with increasing Aβ SUVR. Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in A4 and accelerated cognitive decline as well as brain atrophy in ADNI may help to identify those at the highest risk of accelerated progression of Alzheimer's disease.

The association of subjective sleep characteristics and plasma biomarkers of Alzheimer's disease pathology in older cognitively unimpaired adults with higher amyloid-β burden.

We aimed to investigate the association of subjective sleep characteristics and plasma Alzheimer's disease (AD) biomarkers in older cognitively unimpaired adults with higher amyloid-β (Aβ) burden. Unimpaired cognition was determined by education-adjusted performance for the Mini-Mental State Examination and exclusion of dementia and mild cognitive impairment via standardized neuropsychological tests. We used Pittsburgh Sleep Quality Index (PSQI) to assess subjective sleep quality. The participants also underwent examination of plasma AD biomarkers and 18F-florbetapir PET scan. Correlation and multiple linear regression analyses were used to investigate the association between subjective sleep characteristics and AD biomarkers. A total of 335 participants were included and 114 were Aβ-PET positive. Multivariable regression analysis showed sleep duration > 8h and sleep disturbance were associated with Aβ deposition in total participants. Two multiple linear regression models were applied and the results revealed in participants with Aβ-PET (+), falling asleep at ≥ 22:00 to ≤ 23:00 was associated with higher levels of Aβ42 and Aβ42/40. Other associations with higher Aβ42/40 and standard uptake value ratio contained sleep efficiency value, sleep efficiency ≥ 75%, no/mild daytime dysfunction and PSQI score ≤ 5. Higher p-Tau-181 level was associated with sleep latency > 30min in Aβ-PET (+) group and moderate/severe sleep disturbance in Aβ-PET (-) group. Our data suggests sleep duration ≤ 8h and no/mild sleep disturbance may be related to less Aβ burden. In participants with Aβ deposition, falling asleep at 22:00 to 23:00, higher sleep efficiency (at least ≥ 75%), no/mild daytime dysfunction, sleep latency ≤ 30min, and good sleep quality may help improve AD pathology.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02). Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

DeepAD: A deep learning application for predicting amyloid standardized uptake value ratio through PET for Alzheimer's prognosis.

Amyloid deposition is a vital biomarker in the process of Alzheimer's diagnosis. 18F-florbetapir PET scans can provide valuable imaging data to determine cortical amyloid quantities. However, the process is labor and doctor intensive, requiring extremely specialized education and resources that may not be accessible to everyone, making the amyloid calculation process inefficient. Deep learning is a rising tool in Alzheimer's research which could be used to determine amyloid deposition. Using data from the Alzheimer's Disease Neuroimaging Initiative, we identified 2,980 patients with PET imaging, clinical, and genetic data. We tested various ResNet, EfficientNet, and RegNet convolutional neural networks and later combined the best performing model with Gradient Boosting Decision Tree algorithms to predict standardized uptake value ratio (SUVR) of amyloid in each patient session. We tried several configurations to find the best model tuning for regression-to-SUVR. We found that the RegNet X064 architecture combined with a grid search-tuned Gradient Boosting Decision Tree with 3 axial input slices and clinical and genetic data achieved the lowest loss. Using the mean-absolute-error metric, the loss converged to an MAE of 0.0441, equating to 96.4% accuracy across the 596-patient test set. We showed that this method is more consistent and accessible in comparison to human readers from previous studies, with lower margins of error and substantially faster calculation times. We implemented our deep learning model on to a web application named DeepAD which allows our diagnostic tool to be accessible. DeepAD could be used in hospitals and clinics with resource limitations for amyloid deposition and shows promise for more imaging tasks as well.

Plasma Core Alzheimer’s Disease Biomarkers Predict Amyloid Deposition Burden by Positron Emission Tomography in Chinese Individuals with Cognitive Decline

Blood-based biomarkers have been considered as a promising method for the diagnosis of Alzheimer's disease (AD). The reliability and accuracy of plasma core AD biomarkers, including phosphorylated tau (P-tau181), total tau (T-tau), Aβ42, and Aβ40, have also been confirmed in diagnosing AD and predicting cerebral β-amyloid (Aβ) deposition in Western populations, while fewer research studies have ever been conducted in China's Han population. In this study, we investigated the capability of plasma core AD biomarkers in predicting cerebral Aβ deposition burden among the China Aging and Neurodegenerative Disorder Initiative (CANDI) cohort consisting of cognitively normal (CN), mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Body fluid (plasma and CSF) AD core biomarkers were measured via single-molecule array (Simoa) immunoassay. The global standard uptake value ratio (SUVR) was then calculated by 18F-florbetapir PET, which was divided into positive (+) and negative (-). The most significant correlation between plasma and CSF was plasma P-tau181 (r = 0.526, P < 0.0001). Plasma P-tau181 and P-tau181/T-tau ratio were positively correlated with global SUVR (r = 0.257, P < 0.0001; r = 0.263, P < 0.0001, respectively), while Aβ42 and Aβ42/Aβ40 ratio were negatively correlated with global SUVR (r = -0.346, P < 0.0001; r = -0.407, P < 0.0001, respectively). Interestingly, voxel-wise analysis showed that plasma P-tau181 and P-tau181/T-tau ratio were negatively related to 18F-florbetapir PET in the hippocampus and parahippocampal cortex. The optimal predictive capability in distinguishing all Aβ+ participants from Aβ- participants and MCI+ from MCI- subgroups was the plasma P-tau181/T-tau ratio (AUC = 0.825 and 0.834, respectively). Our study suggested that plasma P-tau181 and P-tau181/T-tau ratio possessed better diagnostic and predictive values than plasma Aβ42 and Aβ42/Aβ40 in this cohort, a finding that may be useful in clinical practices and trials in China.

The relationship between plasma biomarkers and amyloid PET in dementia with Lewy bodies

IntroductionAmyloid-β (Aβ) deposition is common in dementia with Lewy bodies (DLB) and has been associated with more rapid disease progression. An effective biomarker that identified the presence of significant brain Aβ in people with DLB may be useful to identify and stratify participants for research studies and to inform prognosis in clinical practice. Plasma biomarkers are emerging as candidates to fulfil this role. MethodsThirty-two participants with DLB had brain amyloid (18F-florbetapir) PET, of whom 27 also had an MRI to enable the calculation of 18F-florbetapir SUVR. Plasma Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using single molecule array (Simoa). The plasma biomarkers were investigated for correlation with 18F-florbetapir SUVR, discriminant ability to identify Aβ-positive cases based on a predefined SUVR threshold of 1.10 and correlation with subsequent cognitive decline over one year. ResultsAll four plasma markers significantly correlated with 18F-florbetapir SUVR (|β| = 0.40-0.49; p < .05). NfL had the greatest area under the receiver operating characteristic curve to identify Aβ-positive cases (AUROC 0.84 (95% CI 0.66, 1); β = 0.46, p = .001), whereas Aβ42/40 had the smallest (AUROC 0.73 (95% CI 0.52, 0.95); β = −0.47, p = .01). Accuracy was highest when combining all four biomarkers (AUROC 0.92 (95% CI 0.80, 1)).Lower plasma Aβ42/40 was significantly associated with more rapid decline in cognition (β = 0.53, p < .01). ConclusionsPlasma biomarkers have the potential to identify Aβ deposition in DLB. Further work in other cohorts is required to determine and validate optimal cut-offs for these biomarkers.

Spatial Distribution and Hierarchical Clustering of β-Amyloid and Glucose Metabolism in Alzheimer's Disease.

Increased amyloid burden and decreased glucose metabolism are important characteristics of Alzheimer’s disease (AD), but their spatial distribution and hierarchical clustering organization are still poorly understood. In this study, we explored the distribution and clustering organization of amyloid and glucose metabolism based on 18F-florbetapir and 18F-fluorodeoxyglucose PET data from 68 AD patients and 20 cognitively normal individuals. We found that: (i) cortical regions with highest florbetapir binding were the regions with high glucose metabolism; (ii) the percentage changes of amyloid deposition were greatest in the frontal and temporal areas, and the hypometabolism was greatest in the parietal and temporal areas; (iii) brain areas can be divided into three hierarchical clusters by amyloid and into five clusters by metabolism using a hierarchical clustering approach, indicating that adjacent regions are more likely to be grouped into one sub-network; and (iv) there was a significant positive correlation in any pair of amyloid-amyloid and metabolism-metabolism sub-networks, and a significant negative correlation in amyloid-metabolism sub-networks. This may suggest that the influence forms and brain regions of AD on different pathological markers may not be synchronous, but they are closely related.