Distinct Cognitive Trajectories According to Amyloid Positivity in Non-Alzheimer Disease Dementias.

BACKGROUND: The clinical effects of ß-amyloid positivity (Aß+) on copathologies in various dementias remain relatively underexamined. Thus, the present study was conducted to investigate the prevalence and clinical effects of Aß+ in subcortical vascular cognitive impairment (SVCI) and frontotemporal dementia (FTD). PATIENTS AND METHODS: We enrolled SVCI (n = 583), FTD (n = 152), and cognitively unimpaired (CU) participants (n = 1,249) who underwent Aß PET scans. The odds of having Aß+ were subsequently compared among the diagnostic groups (CU, SVCI, and FTD) according to age and apolipoprotein E genotype. Additionally, a linear mixed-effects model was used to investigate the effects of Aß+ on cognitive trajectories in SVCI and FTD. RESULTS: Compared with CU, the SVCI group had a higher prevalence of Aß+ in the 75 to 90 years age group (adjusted odds ratio, 1.97; 95% confidence interval, 1.36-2.85; P < 0.001), as well as within the apolipoprotein E ε3/ε3 group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.63; P = 0.001), whereas the FTD group showed no difference in Aß+ prevalence. Aß+ was associated with a worse cognitive trajectory in SVCI (adjusted ß-coefficient = -0.6424; P < 0.001), but not in FTD. CONCLUSIONS: These findings contribute to our understanding of Aß biomarker traits in various dementias in Korea.

Ethnic differences in the prevalence of amyloid positivity and cognitive trajectories.

INTRODUCTION: We investigated the prevalence of amyloid beta (Aß) positivity (+) and cognitive trajectories in Koreans and non-Hispanic Whites (NHWs). METHODS: We included 5121 Koreans from multiple centers across South Korea and 929 NHWs from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent Aß positron emission tomography and were categorized into cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia stages. Age, sex, education, and apolipoprotein E. genotype were adjusted using multivariable logistic regression and stabilized inverse probability of treatment weights based on the propensity scores to mitigate imbalances in these variables. RESULTS: The prevalence of Aß+ was lower in CU Koreans than in CU NHWs (adjusted odds ratio 0.60). Aß+ Koreans showed a faster cognitive decline than Aß+ NHWs in the CU (B = -0.314, p = .004) and MCI stages (B = -0.385, p < .001). DISCUSSION: Ethnic characteristics of Aß biomarkers should be considered in research and clinical application of Aß-targeted therapies in diverse populations. HIGHLIGHTS: Koreans have a lower prevalence of Aß positivity compared to NHWs in the CU stage. The effects of Alzheimer's risk factors on Aß positivity differ between Koreans and NHWs. Aß-positive (Aß+) Koreans show faster cognitive decline than Aß+ NHWs in the CU and MCI stages.

Distinct effects of blood pressure parameters on Alzheimer's and vascular markers in 1,952 Asian individuals without dementia.

BACKGROUND: Risk factors for cardiovascular disease, including elevated blood pressure, are known to increase risk of Alzheimer's disease. There has been increasing awareness of the relationship between long-term blood pressure (BP) patterns and their effects on the brain. We aimed to investigate the association of repeated BP measurements with Alzheimer's and vascular disease markers. METHODS: We recruited 1,952 participants without dementia between August 2015 and February 2022. During serial clinic visits, we assessed both systolic BP (SBP) and diastolic BP (DBP), and visit-to-visit BP variability (BPV) was quantified from repeated measurements. In order to investigate the relationship of mean SBP (or DBP) with Alzheimer's and vascular markers and cognition, we performed multiple linear and logistic regression analyses after controlling for potential confounders (Model 1). Next, we investigated the relationship of with variation of SBP (or DBP) with the aforementioned variables by adding it into Model 1 (Model 2). In addition, mediation analyses were conducted to determine mediation effects of Alzheimer's and vascular makers on the relationship between BP parameters and cognitive impairment. RESULTS: High Aß uptake was associated with greater mean SBP (ß = 1.049, 95% confidence interval 1.016-1.083). High vascular burden was positively associated with mean SBP (odds ratio = 1.293, 95% CI 1.015-1.647) and mean DBP (1.390, 1.098-1.757). High tau uptake was related to greater systolic BPV (0.094, 0.001-0.187) and diastolic BPV (0.096, 0.007-0.184). High Aß uptake partially mediated the relationship between mean SBP and the Mini-Mental State Examination (MMSE) scores. Hippocampal atrophy mediated the relationship between diastolic BPV and MMSE scores. CONCLUSIONS: Each BP parameter affects Alzheimer's and vascular disease markers differently, which in turn leads to cognitive impairment. Therefore, it is necessary to appropriately control specific BP parameters to prevent the development of dementia. Furthermore, a better understanding of pathways from specific BP parameters to cognitive impairments might enable us to select the managements targeting the specific BP parameters to prevent dementia effectively.

Prediction of Amyloid Positivity in Patients with Subcortical Vascular Cognitive Impairment.

Background: Amyloid-ß (Aß) commonly coexists and impacts prognosis in subcortical vascular cognitive impairment (SVCI). Objective: This study aimed to examine the differences in clinical and neuroimaging variables between Aß-positive and Aß-negative SVCI and to propose a prediction model for Aß positivity in clinically diagnosed SVCI patients. Methods: A total of 130 patients with SVCI were included in model development, and a separate cohort of 70 SVCI patients was used in external validation. The variables for the prediction model were selected by comparing the characteristics of the Aß-negative and Aß-positive SVCI groups. The final model was determined using a stepwise method. The model performance was evaluated using the receiver operating characteristic (ROC) curve and a calibration curve. A nomogram was used for visualization. Results: Among 130 SVCI patients, 70 (53.8%) were Aß-positive. The Aß-positive SVCI group was characterized by older age, tendency to be in the dementia stage, a higher prevalence of APOEɛ4, a lower prevalence of lacune, and more severe medial temporal atrophy (MTA). The final prediction model, which excluded MTA grade following the stepwise method for variable selection, demonstrated good accuracy in distinguishing between Aß-positive and Aß-negative SVCI, with an area under the curve (AUC) of 0.80. The external validation demonstrated an AUC of 0.71. Conclusions: The findings suggest that older age, dementia stage, APOEɛ4 carrier, and absence of lacunes may be predictive of Aß positivity in clinically diagnosed SVCI patients.

Clinical and Pathological Validation of CT-Based Regional Harmonization Methods of Amyloid PET.

PURPOSE: The CT-based regional direct comparison Centiloid (dcCL) method was developed to harmonize and quantify regional ß-amyloid (Aß) burden. In the present study, we aimed to investigate correlations between the CT-based regional dcCL scales and Aß pathological burdens and to validate the clinical utility using thresholds derived from pathological assessment. PATIENTS AND METHODS: We included a pathological cohort of 63 cases and a clinical cohort of 4062 participants, and obtained modified Consortium to Establish a Registry for Alzheimer's Disease criteria (mCERAD) scores by assessment of neuritic plaque burdens in multiple areas of each cortical region. PET and CT images were processed using the CT-based regional dcCL method to calculate scales in 6 distinct regions. RESULTS: The CT-based regional dcCL scales were correlated with neuritic plaque burdens represented by mCERAD scores, globally and regionally ( r = 0.56~0.76). In addition, striatum dcCL scales reflected Aß involvement in the striatum ( P < 0.001). The regional dcCL scales could predict significant Aß deposition in specific brain regions with high accuracy: area under the receiver operating characteristic curve of 0.81-0.97 with an mCERAD cutoff of 1.5 and area under the receiver operating characteristic curve of 0.88-0.93 with an mCERAD cutoff of 0.5. When applying the dcCL thresholds of 1.5 mCERAD scores, the G(-)R(+) group showed lower performances in memory and global cognitive functions and had less hippocampal volume compared with the G(-)R(-) group ( P < 0.001). However, when applying the dcCL thresholds of 0.5 mCERAD scores, there were no differences in the global cognitive functions between the 2 groups. CONCLUSIONS: The thresholds of regional dcCL scales derived from pathological assessments might provide clinicians with a better understanding of biomarker-guided diagnosis and distinguishable clinical phenotypes, which are particularly useful when harmonizing different PET ligands with only PET/CT.

Distinct effects of cholesterol profile components on amyloid and vascular burdens.

BACKGROUND: Cholesterol plays important roles in ß-amyloid (Aß) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aß and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aß and CSVD burdens in a large, non-demented Korean cohort. METHODS: We enrolled 1,175 non-demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aß PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglyceride) level as a predictor and each image marker (Aß uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders. RESULTS: Increased LDL-c levels (ß = 0.014 to 0.115, p = 0.013) were associated with greater Aß uptake, independent of the APOE e4 allele genotype and lipid-lowering medication. Decreased HDL-c levels (ß = - 0.133 to - 0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL-c levels were also associated with decreased hippocampal volume (direct effect ß = - 0.053, p = 0.040), which was partially mediated by Aß uptake (indirect effect ß = - 0.018, p = 0.006). CONCLUSIONS: Our findings highlight that increased LDL-c and decreased HDL-c levels are important risk factors for Aß and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL-c and HDL-c levels is a potential strategy to prevent dementia.

Clinical effects of novel susceptibility genes for beta-amyloid: a gene-based association study in the Korean population.

Amyloid-beta (Aß) is a pathological hallmark of Alzheimer's disease (AD). We aimed to identify genes related to Aß uptake in the Korean population and investigate the effects of these novel genes on clinical outcomes, including neurodegeneration and cognitive impairments. We recruited a total of 759 Korean participants who underwent neuropsychological tests, brain magnetic resonance imaging, 18F-flutemetamol positron emission tomography, and microarray genotyping data. We performed gene-based association analysis, and also performed expression quantitative trait loci and network analysis. In genome-wide association studies, no single nucleotide polymorphism (SNP) passed the genome-wide significance threshold. In gene-based association analysis, six genes (LCMT1, SCRN2, LRRC46, MRPL10, SP6, and OSBPL7) were significantly associated with Aß standardised uptake value ratio in the brain. The three most significant SNPs (rs4787307, rs9903904, and rs11079797) on these genes are associated with the regulation of the LCMT1, OSBPL7, and SCRN2 genes, respectively. These SNPs are involved in decreasing hippocampal volume and cognitive scores by mediating Aß uptake. The 19 enriched gene sets identified by pathway analysis included axon and chemokine activity. Our findings suggest novel susceptibility genes associated with the uptake of Aß, which in turn leads to worse clinical outcomes. Our findings might lead to the discovery of new AD treatment targets.

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.