Development of a prediction model for cognitive impairment of sarcopenia using multimodal neuroimaging in non-demented older adults.

INTRODUCTION: Despite prior research on the association between sarcopenia and cognitive impairment in the elderly, a comprehensive model that integrates various brain pathologies is still lacking. METHODS: We used data from 528 non-demented older adults with or without sarcopenia in the Catholic Aging Brain Imaging (CABI) database, containing magnetic resonance imaging scans, positron emission tomography scans, and clinical data. We also measured three key components of sarcopenia: skeletal muscle index (SMI), hand grip strength (HGS), and the five times sit-to-stand test (5STS). RESULTS: All components of sarcopenia were significantly correlated with global cognitive function, but cortical thickness and amyloid-beta (Aß) retention had distinctive relationships with each measure. In the path model, brain atrophy resulting in cognitive impairment was mediated by Aß retention for SMI and periventricular white matter hyperintensity for HGS, but directly affected by the 5STS. DISCUSSION: Treatments targeting each sub-domain of sarcopenia should be considered to prevent cognitive decline. HIGHLIGHTS: We identified distinct impacts of three sarcopenia measures on brain structure and Aß. Muscle mass is mainly associated with Aß and has an influence on the brain atrophy. Muscle strength linked with periventricular WMH and brain atrophy. Muscle function associated with cortical thinning in specific brain regions. Interventions on sarcopenia may be important to ease cognitive decline in the elderly.

Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

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 (Aß) 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 Aß 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 Aß deposition.

Harmonisation of PET imaging features with different amyloid ligands using machine learning-based classifier.

PURPOSE: In this study, we used machine learning to develop a new method derived from a ligand-independent amyloid (Aß) positron emission tomography (PET) classifier to harmonise different Aß ligands. METHODS: We obtained 107 paired 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) PET images at the Samsung Medical Centre. To apply the method to FMM ligand, we transferred the previously developed FBB PET classifier to test similar features from the FMM PET images for application to FMM, which in turn developed a ligand-independent Aß PET classifier. We explored the concordance rates of our classifier in detecting cortical and striatal Aß positivity. We investigated the correlation of machine learning-based cortical tracer uptake (ML-CTU) values quantified by the classifier between FBB and FMM. RESULTS: This classifier achieved high classification accuracy (area under the curve = 0.958) even with different Aß PET ligands. In addition, the concordance rate of FBB and FMM using the classifier (87.5%) was good to excellent, which seemed to be higher than that in visual assessment (82.7%) and lower than that in standardised uptake value ratio cut-off categorisation (93.3%). FBB and FMM ML-CTU values were highly correlated with each other (R = 0.903). CONCLUSION: Our findings suggested that our novel classifier may harmonise FBB and FMM ligands in the clinical setting which in turn facilitate the biomarker-guided diagnosis and trials of anti-Aß treatment in the research field.

Strictly Lobar Microbleeds Reflect Amyloid Angiopathy Regardless of Cerebral and Cerebellar Compartments.

BACKGROUND AND PURPOSE: We aimed to determine whether lobar cerebellar microbleeds or concomitant lobar cerebellar and deep microbleeds, in the presence of lobar cerebral microbleeds, attribute to underlying advanced cerebral amyloid angiopathy pathology or hypertensive arteriopathy. METHODS: We categorized 71 patients with suspected cerebral amyloid angiopathy markers (regardless of the presence of deep and cerebellar microbleeds) into 4 groups according to microbleed distribution: L (strictly lobar cerebral, n=33), L/LCbll (strictly lobar cerebral and strictly lobar cerebellar microbleeds, n=13), L/Cbll/D (lobar, cerebellar, and deep microbleeds, n=17), and L/D (lobar and deep, n=8). We additionally categorized patients with cerebellar microbleeds into 2 groups according to dentate nucleus involvement: strictly lobar cerebellar (n=16) and dentate (n=14). We then compared clinical characteristics, Aß (amyloid-ß) positivity on PET (positron emission tomography), magnetic resonance imaging cerebral amyloid angiopathy markers, and cerebral small vessel disease burden among groups. RESULTS: The frequency of Aß positivity was higher in the L and L/LCbll groups (81.8% and 84.6%) than in the L/Cbll/D and L/D groups (37.5% and 29.4%; P<0.001), while lacune numbers were lower in the L and L/LCbll groups (1.7±3.3 and 1.7±2.6) than in the L/Cbll/D and L/D groups (8.0±10.3 and 13.4±17.7, P=0.001). The L/LCbll group had more lobar cerebral microbleeds than the L group (93.2±121.8 versus 38.0±40.8, P=0.047). The lobar cerebellar group had a higher Aß positivity (75% versus 28.6%, P=0.011) and lower lacune number (2.3±3.7 versus 8.6±1.2, P=0.041) than the dentate group. CONCLUSIONS: Strictly lobar cerebral and cerebellar microbleeds are related to cerebral amyloid angiopathy, whereas any combination of concurrent lobar and deep microbleeds suggest hypertensive angiopathy regardless of cerebral or cerebellar compartments.

Correction to: A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

Funding information from the original version of this article was incomplete. Complete information is presented here.

A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

PURPOSE: We developed a new method to directly calculate Centiloid (CL) units of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) without conversion to the PiB standardized uptake value ratio (SUVR). METHODS: Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method. RESULTS: Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R2 = 0.97, FMM dcCL = 0.97 × FBB dcCL + 1.64) and the standard method (R2 = 0.97, FMM CLstandard = 0.79 × FBB CLstandard + 1.36). However, the CL variations between FBB and FMM were smaller when calculated by dcCL method (6.15) than when calculated by the previous method (10.22; P = 0.01). CONCLUSIONS: Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Clinical significance of amyloid ß positivity in patients with probable cerebral amyloid angiopathy markers.

PURPOSE: We investigated the frequency and clinical significance of amyloid ß (Aß) positivity on PET in patients with cerebral amyloid angiopathy (CAA). METHODS: We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aß positivity and investigated the effect of Aß positivity on longitudinal cognitive decline. RESULTS: Among the 65 CAA patients, 43 (66.2%) showed Aß PET positivity (Aß+). Patients with Aß+ CAA had more lobar microbleeds (median 9, interquartile range 2-41, vs. 3, 2-8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aß- CAA had more lacunes (1, 0-2, vs. 0, 0-1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aß+ patients (57.1%) than in Aß- patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aß positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models. CONCLUSION: Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aß- on PET. Aß positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aß positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer's disease neuropathological changes.

Associations between Education Years and Resting-state Functional Connectivity Modulated by APOE ε4 Carrier Status in Cognitively Normal Older Adults.

Objective: : Cognitive reserve has emerged as a concept to explain the variable expression of clinical symptoms in the pathology of Alzheimer's disease (AD). The association between years of education, a proxy of cognitive reserve, and resting-state functional connectivity (rFC), a representative intermediate phenotype, has not been explored in the preclinical phase, considering risk factors for AD. We aimed to evaluate whether the relationship between years of education and rFC in cognitively preserved older adults differs depending on amyloid-beta deposition and APOE ε4 carrier status as effect modifiers. Methods: : A total of 121 participants underwent functional magnetic resonance imaging, [18F] flutemetamol positron emission tomography-computed tomography, APOE genotyping, and a neuropsychological battery. Potential interactions between years of education and AD risk factors for rFC of AD-vulnerable neural networks were assessed with whole-brain voxel-wise analysis. Results: : We found a significant education years-by-APOE ε4 carrier status interaction for the rFC from the seed region of the central executive (CEN) and dorsal attention networks. Moreover, there was a significant interaction of rFC between right superior occipital gyrus and the CEN seed region by APOE ε4 carrier status for memory performances and overall cognitive function. Conclusion: : In preclinical APOE ε4 carriers, higher years of education were associated with higher rFC of the AD vulnerable network, but this contributed to lower cognitive function. These results contribute to a deeper understanding of the impact of cognitive reserve on sensitive functional intermediate phenotypic markers in the preclinical phase of AD.

Impact of Apolipoprotein E4 on the Locus Coeruleus Functional Connectivity in Preclinical Alzheimer's Disease.

Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer's disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4). Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-ß (Aß) deposition. Methods: A cohort of 112 cognitively intact individuals, all Aß-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aß deposition on LC FC values. Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aß deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.

Automated Scoring of Alzheimer's Disease Atrophy Scale with Subtype Classification Using Deep Learning-Based T1-Weighted Magnetic Resonance Image Segmentation.

Background: Application of visual scoring scales for regional atrophy in Alzheimer's disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement. Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI). Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability. Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool. Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets.

A multimodal machine learning model for predicting dementia conversion in Alzheimer's disease.

Alzheimer's disease (AD) accounts for 60-70% of the population with dementia. Mild cognitive impairment (MCI) is a diagnostic entity defined as an intermediate stage between subjective cognitive decline and dementia, and about 10-15% of people annually convert to AD. We aimed to investigate the most robust model and modality combination by combining multi-modality image features based on demographic characteristics in six machine learning models. A total of 196 subjects were enrolled from four hospitals and the Alzheimer's Disease Neuroimaging Initiative dataset. During the four-year follow-up period, 47 (24%) patients progressed from MCI to AD. Volumes of the regions of interest, white matter hyperintensity, and regional Standardized Uptake Value Ratio (SUVR) were analyzed using T1, T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRIs, and amyloid PET (αPET), along with automatically provided hippocampal occupancy scores (HOC) and Fazekas scales. As a result of testing the robustness of the model, the GBM model was the most stable, and in modality combination, model performance was further improved in the absence of T2-FLAIR image features. Our study predicts the probability of AD conversion in MCI patients, which is expected to be useful information for clinician's early diagnosis and treatment plan design.

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

Background: 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 ß-amyloid (Aß) uptake and global Aß status. Methods: 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. Results: A total of 62 (6.4%) subjects showed increased focal Aß uptake with subthreshold global Aß status [global (-) and focal (+) Aß 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 Aß involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aß involvement G(-)F(+). Conclusion: Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aß uptake and global Aß status. Thus, researchers and clinicians should pay more attention to focal increased Aß uptake in addition to global Aß status.

Modulation of associations between education years and cortical volume in Alzheimer's disease vulnerable brain regions by Aß deposition and APOE ε4 carrier status in cognitively normal older adults.

Background: Education years, as a measure of cognitive reserve, have been shown to affect the progression of Alzheimer's disease (AD), both pathologically and clinically. However, inconsistent results have been reported regarding the association between years of education and intermediate structural changes in AD-vulnerable brain regions, particularly when AD risk factors were not considered during the preclinical phase. Objective: This study aimed to examine how Aß deposition and APOE ε4 carrier status moderate the relationship between years of education and cortical volume in AD-vulnerable regions among cognitively normal older adults. Methods: A total of 121 participants underwent structural MRI, [18F] flutemetamol PET-CT imaging, and neuropsychological battery assessment. Multiple regression analysis was conducted to examine the interaction between years of education and the effects of potential modifiers on cortical volume. The associations between cortical volume and neuropsychological performance were further explored in subgroups categorized based on AD risk factors. Results: The cortical volume of the left lateral occipital cortex and bilateral fusiform gyrus demonstrated a significant differential association with years of education, depending on the presence of Aß deposition and APOE ε4 carrier status. Furthermore, a significant relationship between the cortical volume of the bilateral fusiform gyrus and AD-nonspecific cognitive function was predominantly observed in individuals without AD risk factors. Conclusion: AD risk factors exerted varying influences on the association between years of education and cortical volume during the preclinical phase. Further investigations into the long-term implications of these findings would enhance our understanding of cognitive reserves in the preclinical stages of AD.

Predicting conversion of brain ß-amyloid positivity in amyloid-negative individuals.

BACKGROUND: Cortical deposition of ß-amyloid (Aß) plaque is one of the main hallmarks of Alzheimer's disease (AD). While Aß positivity has been the main concern so far, predicting whether Aß (-) individuals will convert to Aß (+) has become crucial in clinical and research aspects. In this study, we aimed to develop a classifier that predicts the conversion from Aß (-) to Aß (+) using artificial intelligence. METHODS: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort regarding patients who were initially Aß (-). We developed an artificial neural network-based classifier with baseline age, gender, APOE ε4 genotype, and global and regional standardized uptake value ratios (SUVRs) from positron emission tomography. Ten times repeated 10-fold cross-validation was performed for model measurement, and the feature importance was assessed. To validate the prediction model, we recruited subjects at the Samsung Medical Center (SMC). RESULTS: A total of 229 participants (53 converters) from the ADNI dataset and a total of 40 subjects (10 converters) from the SMC dataset were included. The average area under the receiver operating characteristic values of three developed models are as follows: Model 1 (age, gender, APOE ε4) of 0.674, Model 2 (age, gender, APOE ε4, global SUVR) of 0.814, and Model 3 (age, gender, APOE ε4, global and regional SUVR) of 0.841. External validation result showed an AUROC of 0.900. CONCLUSION: We developed prediction models regarding Aß positivity conversion. With the growing recognition of the need for earlier intervention in AD, the results of this study are expected to contribute to the screening of early treatment candidates.

Ethnic differences in the frequency of ß-amyloid deposition in cognitively normal individuals.

We investigated which factors might explain the differences between the frequencies of brain ß-amyloid (Aß) deposition in Korean and European cognitively normal individuals (CNs). We recruited 434 Korean CNs from the Samsung Medical Center (SMC) and 323 European CNs from the US Alzheimer's Disease Neuroimaging Initiative (ADNI). The Korean CNs showed lower education duration (11.8 ± 4.8 years vs. 16.8 ± 2.5 years, p < 0.001) than the European CNs. The frequency of Aß (+) was higher in the European CNs (32.8%) than in the Korean CNs (20.0%; p < 0.001). In the SMC genome-wide association study (GWAS), 10 variants (including rs7481773 on chromosome 11, located near the brain-derived neurotrophic factor gene) exceeded the genome-wide significance level (p < 5 × 10-8). Especially, rs7481773 carriers showed more rapid decline in memory function than non-carriers (p = 0.048). However, this association was not observed in the ADNI GWAS. Our findings suggested that the different frequencies of Aß (+) between CN Koreans and Europeans might be related to decreased cognitive reserve or genetic factors.

Development and clinical validation of CT-based regional modified Centiloid method for amyloid PET.

BACKGROUND: The standard Centiloid (CL) method was proposed to harmonize and quantify global 18F-labeled amyloid beta (Aß) PET ligands using MRI as an anatomical reference. However, there is need for harmonizing and quantifying regional Aß uptakes between ligands using CT as an anatomical reference. In the present study, we developed and validated a CT-based regional direct comparison of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) Centiloid (rdcCL). METHODS: For development of MRI-based or CT-based rdcCLs, the cohort consisted of 63 subjects (20 young controls (YC) and 18 old controls (OC), and 25 participants with Alzheimer's disease dementia (ADD)). We performed a direct comparison of the FMM-FBB rdcCL method using MRI and CT images to define a common target region and the six regional VOIs of frontal, temporal, parietal, posterior cingulate, occipital, and striatal regions. Global and regional rdcCL scales were compared between MRI-based and CT-based methods. For clinical validation, the cohort consisted of 2245 subjects (627 CN, 933 MCI, and 685 ADD). RESULTS: Both MRI-based and CT-based rdcCL scales showed that FMM and FBB were highly correlated with each other, globally and regionally (R2 = 0.96~0.99). Both FMM and FBB showed that CT-based rdcCL scales were highly correlated with MRI-based rdcCL scales (R2 = 0.97~0.99). Regarding the absolute difference of rdcCLs between FMM and FBB, the CT-based method was not different from the MRI-based method, globally or regionally (p value = 0.07~0.95). In our clinical validation study, the global negative group showed that the regional positive subgroup had worse neuropsychological performance than the regional negative subgroup (p < 0.05). The global positive group also showed that the striatal positive subgroup had worse neuropsychological performance than the striatal negative subgroup (p < 0.05). CONCLUSIONS: Our findings suggest that it is feasible to convert regional FMM or FBB rdcSUVR values into rdcCL scales without additional MRI scans. This allows a more easily accessible method for researchers that can be applicable to a variety of different conditions.

Gender-specific relationship between thigh muscle and fat mass and brain amyloid-ß positivity.

BACKGROUND: The relationship of specific body composition in the thighs and brain amyloid-beta (Aß) deposition remained unclear, although there were growing evidence that higher muscle and fat mass in thighs had a protective effect against cardiometabolic syndromes. To determine whether muscle mass and fat mass in the thighs affected amyloid-beta (Aß) positivity differently in relation to gender, we investigated the association of muscle mass and fat mass with Aß positivity using positron emission tomography (PET) in individuals without dementia. METHODS: We recruited 240 participants (134 [55.8%] males, 106 [44.2%] females) without dementia ≥45 years of age who underwent Aß PET, bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) scans of the hip in the health promotion center at Samsung Medical Center in Seoul, Korea. Lower extremity skeletal muscle mass index (LASMI) was measured using BIA, and gluteofemoral fat percentage (GFFP) was estimated using DEXA scans of the hip. We investigated the associations of LASMI and GFFP with Aß positivity using logistic regression analyses after controlling for age, APOE4 genotype, and cognitive stage. RESULTS: Higher muscle mass in the thighs, measured as LASMI (odds ratio [OR]=0.27, 95% confidence interval [CI] 0.08 to 0.84, p=0.031) was associated with a lesser risk of Aß positivity in only females. Higher fat mass in the thighs, measured as GFFP (OR=0.84, 95% CI 0.73 to 0.95, p=0.008) was associated with a lesser risk of Aß positivity in only males. However, the association between LAMSI (p for interaction= 0.810), GFFP (p for interaction= 0.075) and Aß positivity did not significantly differ by gender. Furthermore, LAMSI only negatively correlated with centiloid (CL) values in females (r=-0.205, p=0.037), and GFFP only negatively correlated with CL values only in males (r=-0.253, p=0.004). CONCLUSIONS: Our findings highlight the importance of recognizing that gender differences exist with respect to the specific body composition to potentially protect against Aß deposition. Therefore, our results may help in designing gender-specific strategies for controlling body composition to prevent Aß deposition.

Independent effect of body mass index variation on amyloid-ß positivity.

Objectives: The relationship of body mass index (BMI) changes and variability with amyloid-ß (Aß) deposition remained unclear, although there were growing evidence that BMI is associated with the risk of developing cognitive impairment or AD dementia. To determine whether BMI changes and BMI variability affected Aß positivity, we investigated the association of BMI changes and BMI variability with Aß positivity, as assessed by PET in a non-demented population. Methods: We retrospectively recruited 1,035 non-demented participants ≥50 years of age who underwent Aß PET and had at least three BMI measurements in the memory clinic at Samsung Medical Center. To investigate the association between BMI change and variability with Aß deposition, we performed multivariable logistic regression. Further distinctive underlying features of BMI subgroups were examined by employing a cluster analysis model. Results: Decreased (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.16-2.42) or increased BMI (OR = 1.60, 95% CI 1.11-2.32) was associated with a greater risk of Aß positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI variability. A greater BMI variability (OR = 1.73, 95% CI 1.07-2.80) was associated with a greater risk of Aß positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI change. We also identified BMI subgroups showing a greater risk of Aß positivity. Conclusion: Our findings suggest that participants with BMI change, especially those with greater BMI variability, are more vulnerable to Aß deposition regardless of baseline BMI. Furthermore, our results may contribute to the design of strategies to prevent Aß deposition with respect to weight control.

18F-THK5351 PET Positivity and Longitudinal Changes in Cognitive Function in ß-Amyloid-Negative Amnestic Mild Cognitive Impairment.

PURPOSE: Neuroinflammation is considered an important pathway associated with several diseases that result in cognitive decline. 18F-THK5351 positron emission tomography (PET) signals might indicate the presence of neuroinflammation, as well as Alzheimer's disease-type tau aggregates. ß-amyloid (Aß)-negative (Aß-) amnestic mild cognitive impairment (aMCI) may be associated with non-Alzheimer's disease pathophysiology. Accordingly, we investigated associations between 18F-THK5351 PET positivity and cognitive decline among Aß- aMCI patients. MATERIALS AND METHODS: The present study included 25 amyloid PET negative aMCI patients who underwent a minimum of two follow-up neuropsychological evaluations, including clinical dementia rating-sum of boxes (CDR-SOB). The patients were classified into two groups: 18F-THK5351-positive and -negative groups. The present study used a linear mixed effects model to estimate the effects of 18F-THK5351 PET positivity on cognitive prognosis among Aß- aMCI patients. RESULTS: Among the 25 Aß- aMCI patients, 10 (40.0%) were 18F-THK5351 positive. The patients in the 18F-THK5351-positive group were older than those in the 18F-THK5351-negative group (77.4±2.2 years vs. 70.0±5.5 years; p<0.001). There was no difference between the two groups with regard to the proportion of apolipoprotein E ε4 carriers. Interestingly, however, the CDR-SOB scores of the 18F-THK5351-positive group deteriorated at a faster rate than those of the 18F-THK5351-negative group (B=0.003, p=0.033). CONCLUSION: The results of the present study suggest that increased 18F-THK5351 uptake might be a useful predictor of poor prognosis among Aß- aMCI patients, which might be associated with increased neuroinflammation (ClinicalTrials.gov NCT02656498).