Positive Amyloid Positron Emission Tomography Research Articles

Combining Blood-Based Biomarkers and Structural MRI Measurements to Distinguish Persons with and without Significant Amyloid Plaques.

Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Association of Serum Liver Enzymes with Brain Amyloidopathy and Cognitive Performance.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles in the brain. Emerging evidence has suggested potential interactions between the brain and periphery, particularly the liver, in regulating Aβ homeostasis. This study aimed to investigate the association of serum liver enzymes with brain amyloidopathy and cognitive performance in patients with complaints of cognitive decline. A total of 1,036 patients (mean age 74 years, 66.2% female) with subjective cognitive decline, mild cognitive impairment, AD dementia, and other neurodegenerative diseases were included using the Smart Clinical Data Warehouse. Amyloid positron emission tomography (PET) imaging, comprehensive neuropsychological evaluations, and measurements of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and albumin, were assessed. After propensity score matching, logistic and linear regression analyses were used to investigate the associations between liver enzymes, amyloid status, and cognitive performance. Additionally, a machine learning approach was used to assess the classification performance of liver enzymes in predicting amyloid PET positivity. Lower ALT levels and higher AST-to-ALT ratios were significantly associated with amyloid PET positivity and AD diagnosis. The AST-to-ALT ratio was also significantly associated with poor memory function. Machine learning analysis revealed that the classification performance of amyloid status (AUC = 0.642) for age, sex, and apolipoprotein E ɛ4 carrier status significantly improved by 6.2% by integrating the AST-to-ALT ratio. These findings highlight the potential association of liver function on AD and its potential as a diagnostic and therapeutic implications.

Alterations in cognitive function and blood biomarkers following transcranial direct current stimulation in patients with amyloid positron emission tomography-positive Alzheimer's disease: a preliminary study.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline. To address this, we conducted a randomized, double-blinded, sham-controlled study to investigate the therapeutic potential of transcranial direct current stimulation (tDCS) on patients with amyloid positron emission tomography (PET)- positive AD. Participants already undergoing pharmacological treatment and testing positive for amyloid PET were divided into Active-tDCS (n = 8) and Sham-tDCS (n = 8) groups. For 12 weeks, participants or their caregivers administered daily bi-frontal tDCS (YMS-201B+, Ybrain Inc., Seongnam, Korea) at home (2 mA, 30 min). Pre- and post-intervention assessments included neuropsychological tests and blood sample measurements for oligomerized beta-amyloid. The Active-tDCS group demonstrated significant improvements in cognitive domains such as language abilities, verbal memory, and attention span and in frontal lobe functions compared to the Sham-tDCS group. Furthermore, the Active-tDCS group showed a marked reduction in post-intervention plasma Aβ oligomerization tendency level, suggesting changes in pivotal AD-associated biomarkers. Our results emphasize the potential therapeutic benefits of tDCS for mild AD patients with amyloid PET positivity and stress the urgency for broader research, considering the global challenges of dementia and the need to pursue innovative therapeutic strategies.

A multivariate MRI model of Alzheimer’s disease risk is associated with clinical diagnosis, PET imaging, and plasma biomarkers in a mixed dementia sample

AbstractBackgroundWe sought to validate two structural MRI‐based brain health models: Spatial Pattern of Atrophy for REcognition of Alzheimer’s disease (SPARE‐AD) and SPARE‐Brain Age Gap (SPARE‐BAG), which estimates the discrepancy between biological brain age and chronological age. These models' generalization to non‐amnestic AD (naAD) syndromes and associations with positron emission tomography (PET) and plasma biomarkers remain underinvestigated. We hypothesized that SPARE‐AD scores in naAD would be lower (less abnormal) than in amnestic AD (aAD) but elevated (more abnormal) relative to controls; and that SPARE‐AD but not SPARE‐BAG scores would be associated with PET and plasma biomarkers of AD.MethodSPARE‐AD and SPARE‐BAG scores were estimated for each of 1607 MRI scans from 277 cognitively normal adults (62.8% female; mean age = 69.5 years) and 902 clinical participants (54.2% female; mean age = 73.1 years), including 585 with amnestic mild cognitive impairment (aMCI) or aAD; 56 with naAD syndromes; 28 with vascular disease; 28 with Lewy body disorders (LBD); 18 with suspected frontotemporal lobar degeneration (FTLD); 56 with non‐amnestic MCI of uncertain etiology; and 131 with other clinical diagnoses. We used mixed effects models adjusting for age, sex, and global cognition to test group differences in SPARE‐AD and SPARE‐BAG. Additionally, we assessed associations with tau (n = 122) and amyloid‐beta (n = 199) PET imaging and plasma‐based phosphorylated tau‐181 (p‐tau181) and glial fibrillary acidic protein (GFAP) (n = 358).ResultSPARE‐AD scores were elevated vs. controls in aMCI/aAD, naAD, vascular disease, FTLD, and naMCI (all p<0.003) but not in LBD or other diagnoses (p>0.1). NaAD patients had lower SPARE‐AD (p<0.02) but higher SPARE‐BAG scores (p<0.02) than aMCI/aAD patients. SPARE‐AD scores were positively associated with mean cortical tau PET uptake, amyloid PET positivity, and plasma p‐tau181 and GFAP (all p<0.001). In contrast, SPARE‐BAG scores were not associated with PET or plasma biomarkers (all p>0.05).ConclusionSPARE‐AD values for naAD syndromes were intermediate between those of controls and aMCI/AD patients, likely reflecting divergent, partially overlapping cortical atrophy relative to aAD. PET and plasma biomarkers of AD neuropathologic change were associated with SPARE‐AD but not with SPARE‐BAG scores, suggesting SPARE‐BAG reflects age‐related atrophy that is largely independent of AD.

A Comprehensive, Community‐Engaged Recruitment Strategy to Increase Minority Representation in New IDEAS – an Amyloid Imaging Study

AbstractBackgroundAlthough Black and Hispanic/Latino people have higher rates of clinical Alzheimer disease (AD), evidence indicates lower proportions and odds of positive amyloid positron emission tomography (PET). This may indicate differences in etiology of cognitive impairment, which has implications for prevention and treatment (ie, anti‐amyloid treatments). Unfortunately, Black and Hispanic/Latino people are underrepresented in AD research.MethodTo evaluate amyloid PET in a diverse sample, we designed culturally‐informed, community‐engaged recruitment strategies for New IDEAS (Imaging Dementia—Evidence for Amyloid Scanning), an observational, open‐label, longitudinal cohort study of beta‐amyloid PET. New IDEAS intends to recruit 7,000 U.S. Medicare beneficiaries with mild cognitive impairment (MCI) or dementia including 2,000 Black/African American and 2,000 Latino/Hispanic individuals. To ensure diversity, we developed a comprehensive recruitment strategy using a diverse, culturally‐trained staff that includes:• Identifying Dementia Specialists experienced recruiting minorities• Embedding high‐impact community engagement in select regions• Increasing capacity of specialists and PET facilities to engage minorities• Increasing pipeline of referrals to Dementia Specialists• Creating a culturally‐informed awareness campaignResultNew IDEAS has enrolled 4,524 participants including 954 (21.1%) Black/African American, and 842 (18.6%) Hispanic/Latinx. Median age is 76 years; 54% are female. More Black/African American (46.6%) and Hispanic/Latinx (42.6%) participants had a dementia diagnosis compared to the overall cohort (33.9%). More Black/African American (37.4%) and Hispanic/Latinx (37%) participants were enrolled in Medicare Advantage compared to the overall cohort (19.5%).During implementation, we encountered additional barriers to minority participation including: dementia specialists and PET facilities located greater distance from minority neighborhoods, lack of transportation to visits, fewer academic medical sites registered, concerns about co‐pays, and dementia specialists not accepting new patients. New strategies are being implemented to address some of barriers including coverage of co‐pays and assistance with transportation.ConclusionNew IDEAS has enrolled more Black/African American and Hispanic/Latinx participants than any amyloid PET study published to date. Despite some success with minority enrollment, recruitment has been hampered by underlying structural barriers such as lack of access to dementia care in minority communities and higher Medicare Advantage rates. Additional resources and policy changes are needed to allow more equitable access to research and dementia care.

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by>20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Amyloid Positron Emission Tomography and Subsequent Health Care Use Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia

Results of amyloid positron emission tomography (PET) have been shown to change the management of patients with mild cognitive impairment (MCI) or dementia who meet Appropriate Use Criteria (AUC). To determine if amyloid PET is associated with reduced hospitalizations and emergency department (ED) visits over 12 months in patients with MCI or dementia. This nonrandomized controlled trial analyzed participants in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, an open-label, multisite, longitudinal study that enrolled participants between February 2016 and December 2017 and followed up through December 2018. These participants were recruited at 595 clinical sites that provide specialty memory care across the US. Eligible participants were Medicare beneficiaries 65 years or older with a diagnosis of MCI or dementia within the past 24 months who met published AUC for amyloid PET. Each IDEAS study participant was matched to a control Medicare beneficiary who had not undergone amyloid PET. Data analysis was conducted on December 13, 2022. Participants underwent amyloid PET at imaging centers. The primary end points were the proportions of patients with 12-month inpatient hospital admissions and ED visits. One of 4 secondary end points was the rate of hospitalizations and rate of ED visits in participants with positive vs negative amyloid PET results. Health care use was ascertained from Medicare claims data. The 2 cohorts (IDEAS study participants and controls) each comprised 12 684 adults, including 6467 females (51.0%) with a median (IQR) age of 77 (73-81) years. Over 12 months, 24.0% of the IDEAS study participants were hospitalized, compared with 25.1% of the matched control cohort, for a relative reduction of -4.49% (97.5% CI, -9.09% to 0.34%). The 12-month ED visit rates were nearly identical between the 2 cohorts (44.8% in both IDEAS study and control cohorts) for a relative reduction of -0.12% (97.5% CI, -3.19% to 3.05%). Both outcomes fell short of the prespecified effect size of 10% or greater relative reduction. Overall, 1467 of 6848 participants (21.4%) with positive amyloid PET scans were hospitalized within 12 months compared with 1081 of 4209 participants (25.7%) with negative amyloid PET scans (adjusted odds ratio, 0.83; 95% CI, 0.78-0.89). Results of this nonrandomized controlled trial showed that use of amyloid PET was not associated with a significant reduction in 12-month hospitalizations or ED visits. Rates of hospitalization were lower in patients with positive vs negative amyloid PET results.

Predicting amyloid PET positivity using plasma p-tau181 and other blood-based biomarkers.

This study aimed to determine the efficacy of combining plasma phosphorylated tau (p-tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Biomarkers were measured using a single-molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE-V). In the Asan cohort, after adjusting for age and sex, p-tau181 (AUC=0.854) or APOE ε4 status (AUC=0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best-fit model included the plasma p-tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE-V cohort. Additionally, in the KBASE-V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC=0.768) and mild cognitive impairment (MCI) (AUC=0.997) participants. Plasma p-tau181 showed a high performance in determining Aβ-PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

Sex differences in the structural rich-club connectivity in patients with Alzheimer's disease.

Alzheimer's disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD. In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis. We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia. Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.

Utility of amyloid PET Imaging in a Memory Clinic.

There is greater interest in amyloid biomarker for the diagnosis of Alzheimer disease (AD) with the recent Food and Drug Administration approval of amyloid-targeted therapy. The goal of this study was to assess the clinical utility of amyloid positron emission tomography (PET) in clinically ambiguous cases of cognitive impairment by examining outcomes of patients enrolled in the Imaging Dementia-Evidence of Amyloid Scanning study at 2 academic institutions. Of the 112 patients in the study, 66.1% (n=74) of patients had a positive amyloid PET scan, and 33.96% (n=38) had a negative amyloid PET scan. Lower cognitive test scores were predictive of positive amyloid PET scan ( P =0.001). Eighty-two percent (92/112) of the patients were seen for follow-up. Of the 30 patients with negative amyloid PET scan results, 90% had a diagnosis of non-AD etiology after receiving the negative results, suggesting a negative amyloid scan can be used to rule out AD diagnosis.

Prediction of amyloid positron emission tomography positivity using multiple regression analysis of quantitative susceptibility mapping

PurposeTo develop a method for predicting amyloid positron emission tomography (PET) positivity based on multiple regression analysis of quantitative susceptibility mapping (QSM). Materials and methodsThis prospective study included 39 patients with suspected dementia from four centers. QSM images were obtained through a 3-T, three-dimensional radiofrequency-spoiled gradient-echo sequence with multiple echoes. The cortical standard uptake value ratio (SUVR) was obtained using amyloid PET with 18F-flutemetamol, and susceptibility in the brain regions was obtained using QSM. A multiple regression model to predict cortical SUVR was constructed based on susceptibilities in multiple brain regions, with the constraint that cortical SUVR and susceptibility were positively correlated. The discrimination performance of the Aβ-positive and Aβ-negative cohorts was evaluated based on the predicted SUVR using the area under the receiver operating characteristic curve (AUC) and Mann–Whitney U test. ResultsThe correlation coefficients between true and predicted SUVR were increased by incorporating the constraint, and the AUC to discriminate between the Aβ-positive and Aβ-negative cohorts reached to 0.79 (p < 0.01). ConclusionThese preliminary results suggest that a QSM-based multiple regression model can predict amyloid PET positivity with fair accuracy.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

Do radiomics or diffusion-tensor images provide additional information to predict brain amyloid-beta positivity?

The aim of the present study was to predict amyloid-beta positivity using a conventional T1-weighted image, radiomics, and a diffusion-tensor image obtained by magnetic resonance imaging (MRI). We included 186 patients with mild cognitive impairment (MCI) who underwent Florbetaben positron emission tomography (PET), MRI (three-dimensional T1-weighted and diffusion-tensor images), and neuropsychological tests at the Asan Medical Center. We developed a stepwise machine learning algorithm using demographics, T1 MRI features (volume, cortical thickness and radiomics), and diffusion-tensor image to distinguish amyloid-beta positivity on Florbetaben PET. We compared the performance of each algorithm based on the MRI features used. The study population included 72 patients with MCI in the amyloid-beta-negative group and 114 patients with MCI in the amyloid-beta-positive group. The machine learning algorithm using T1 volume performed better than that using only clinical information (mean area under the curve [AUC]: 0.73 vs. 0.69, p < 0.001). The machine learning algorithm using T1 volume showed better performance than that using cortical thickness (mean AUC: 0.73 vs. 0.68, p < 0.001) or texture (mean AUC: 0.73 vs. 0.71, p = 0.002). The performance of the machine learning algorithm using fractional anisotropy in addition to T1 volume was not better than that using T1 volume alone (mean AUC: 0.73 vs. 0.73, p = 0.60). Among MRI features, T1 volume was the best predictor of amyloid PET positivity. Radiomics or diffusion-tensor images did not provide additional benefits.

Plasma amyloid‐β oligomerization tendency predicts amyloid PET positivity

AbstractBackgroundAmong other emerging amyloid‐targeting blood‐based biomarkers, Multimer Detection System‐Oligomeric Amyloid‐β (MDS‐OAβ) measures dynamic changes in concentration of oligomeric amyloid‐β (OAβ), which is considered the main pathogenic culprit of Alzheimer’s disease (AD), in plasma after spiking with synthetic amyloid‐β (Aβ). We aimed to investigate predictability of MDS‐OAβ on amyloid Positron Emission Tomography (PET) positivity.MethodA total of 96 subjects who visited Seoul National University Bundang Hospital for medical check‐up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAβ concentration was measured by MDS‐OAβ. In the previous validation study, 0.78ng/ml was established as the cut‐off value and the plasma OAβ concentration higher than or equal to the cut‐off value was defined MDS‐OAβ positive.ResultMDS‐OAβ positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776–0.933). Adding MDS‐OAβ positivity to prediction models including age, MMSE score, and APOE ε4 status improved the performance up to the AUC value of 0.926 (95% CI 0.871–0.980).ConclusionThe Aβ oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and when it is combined with age, MMSE score, and APOE ε4 status, the predictability was improved substantially. This suggests the potential of MDS‐OAβ as a useful initial stage test in clinical and research field of AD.

Spectral power ratio as a measure of EEG changes in mild cognitive impairment due to Alzheimer’s disease: a case-control study

Adopting preventive strategies in individuals with subclinical Alzheimer’s disease (AD) has the potential to delay dementia onset and reduce healthcare costs. Thus, it is extremely important to identify inexpensive, scalable, sensitive, and specific markers to track disease progression. The electroencephalography spectral power ratio (SPR: the fast to slow spectral power ratio), a measure of the shift in power distribution from higher to lower frequencies, holds potential for aiding clinical practice. The SPR is altered in patients with AD, correlates with cognitive functions, and can be easily implemented in clinical settings. However, whether the SPR is sensitive to pathophysiological changes in the prodromal stage of AD is unclear. We explored the SPR of individuals diagnosed with amyloid-positive amnestic mild cognitive impairment (Aβ+aMCI) and its association with both cognitive function and amyloid load. The SPR was lower in Aβ+aMCI than in the cognitively unimpaired individuals and correlated with executive function scores but not with amyloid load. Hypothesis-generating analyses suggested that aMCI participants with a lower SPR had an increased probability of a positive amyloid positron emission tomography. Future research may explore the potential of this measure to classify aMCI individuals according to their AD biomarker status.

Blood β-synuclein is related to amyloid PET positivity in memory clinic patients.

β-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-β(Αβ) pathology is unclear. We investigated the association of plasma β-synuclein levels with [18F] flutemetamol positron emission tomography (PET) in patients with AD dementia (n=51), mild cognitive impairment (MCI-Aβ+n=18, MCI-Aβ-n=30), non-AD dementias (n=22), and non-demented controls (n=5). Plasma β-synuclein levels were higher in Aβ+ (AD dementia, MCI-Aβ+) than in Aβ- subjects (non-AD dementias, MCI-Aβ-) with good discrimination of Aβ+ from Aβ- subjects and prediction of Aβ status in MCI individuals. A positive correlation between plasma β-synuclein and Aβ PET was observed in multiple cortical regions across all lobes. Plasma β-synuclein demonstrated discriminative properties for Aβ PET positive and negative subjects. Our data underline that β-synuclein is not a direct marker of Aβ pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. Blood and CSF β-synuclein levels are higher in Aβ+ than in Aβ- subjects. Blood β-synuclein level correlates with amyloid PET positivity in multiple regions. Blood β-synuclein predicts Aβ status in MCI individuals.

A Pilot Study on Cerebral Blood Flow and Mini-Mental State Examination to Predict Amyloid Deposition in Preclinical Alzheimer's Disease.

Earlier differential diagnosis of dementia remains a major challenge. Although amyloid deposition by positron emission tomography is an emerging standard for the diagnosis of Alzheimer's disease, it is too expensive for routine use in clinical settings. We conducted a pilot study on the potential usefulness of single-photon emission computed tomography and the Mini-Mental State Examination to predict amyloid positron emission tomography positivity in preclinical Alzheimer's disease. Eighteen subjects, including 11 with mild cognitive impairment and 7 with subjective cognitive decline, underwent 18F-florbetapir positron emission tomography, 99mTc-ethylcysteinate dimer cerebral perfusion single-photon emission computed tomography, and the Mini-Mental State Examination. For the assessment of amyloid deposition, visual judgment as a qualitative method and a semiautomatic software analysis as a quantitative method were used. Six subjects were judged as amyloid positive, including 4 mild cognitive impairment and 2 subjective cognitive decline subjects. Compared to the amyloid positron emission tomography-negative group, this group showed a statistically significant difference in the Mini-Mental State Examination recall score [2 (1 : 3) vs. 3 (2 : 3), P = .041] and single-photon emission computed tomography findings from the amyloid-negative group. In the mild cognitive impairment subgroup, correlations were found between amyloid deposition and single-photon emission computed tomography indicators, while in the subjective cognitive decline subgroup, only the Mini-Mental State Examination recall score correlated with amyloid deposition. The Mini-Mental State Examination recall score and single-photon emission computed tomography indicators may be worthwhile for further evaluation as predictors of amyloid deposition in the preclinical stage.

Contribution of clinical information to the predictive performance of plasma β-amyloid levels for amyloid positron emission tomography positivity.

Early detection of β-amyloid (Aβ) accumulation, a major biomarker for Alzheimer's disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aβ for predicting Aβ deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aβ is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aβ and CSF Aβ levels for Aβ PET positivity. We recruited 488 participants who underwent both plasma Aβ and Aβ PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aβ and Aβ PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aβ and CSF Aβ, respectively, logistic regression and receiver operating characteristic analyses were performed. When predicting Aβ PET status, both plasma Aβ42/40 ratio and CSF Aβ42 showed high accuracy (plasma Aβ area under the curve (AUC) 0.814; CSF Aβ AUC 0.848). In the plasma Aβ models, the AUC values were higher than plasma Aβ alone model, when the models were combined with either cognitive stage (p < 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aβ models, when these variables were added. Plasma Aβ might be a useful predictor of Aβ deposition on PET status as much as CSF Aβ, particularly when considered with clinical information such as APOE genotype and cognitive stage.

Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data.

Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer's disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18-9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.