Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics.

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-ß (Aß), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aß, measured using positron emission tomography (PET), examine the accuracy of plasma Aß to predict brain Aß positivity, and the relation of APOE ɛ4 with plasma Aß. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aß42/Aß40 ratio measured with Simoa. Brain Aß burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aß42/Aß40 ratio was inversely associated with global Aß SUVR (ß= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aß positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aß42/Aß40 ratio in relation to brain Aß positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aß42/Aß40 ratio and a higher Aß positivity determined with the Aß42/Aß40 ratio threshold of 0.060. CONCLUSION: Plasma Aß42/Aß40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

Neuroimaging biomarkers of cognitive recovery after ischemic stroke.

Post-stroke cognitive impairment affects more than one-third of patients after an ischemic stroke (IS). Identifying markers of potential cognitive recovery after ischemic stroke can guide patients' selection for treatments, enrollment in clinical trials, and cognitive rehabilitation methods to restore cognitive abilities in post-stroke patients. Despite the burden of post-stroke cognitive impairment, biomarkers of cognitive recovery are an understudied area of research. This narrative review summarizes and critically reviews the current literature on the use and utility of neuroimaging as a predictive biomarker of cognitive recovery after IS. Most studies included in this review utilized structural Magnetic Resonance Imaging (MRI) to predict cognitive recovery after IS; these studies highlighted baseline markers of cerebral small vessel disease and cortical atrophy as predictors of cognitive recovery. Functional Magnetic Resonance Imaging (fMRI) using resting-state functional connectivity and Diffusion Imaging are potential biomarkers of cognitive recovery after IS, although more precise predictive tools are needed. Comparison of these studies is limited by heterogeneity in cognitive assessments. For all modalities, current findings need replication in larger samples. Although no neuroimaging tool is ready for use as a biomarker at this stage, these studies suggest a clinically meaningful role for neuroimaging in predicting post-stroke cognitive recovery.

Metabolic Syndrome and Cognitive Function.

PURPOSE OF REVIEW: Metabolic syndrome (MetS) is a cluster of cardiovascular disease risk factors that are related to several adverse health outcomes, including poor cognitive function. This review seeks to summarize and critically review select recent findings on the association between MetS and cognition. RECENT FINDINGS: MetS was associated with lower domain-specific and global cognitive function in most cross-sectional studies, but findings from longitudinal studies are not consistent. The associations varied depending on age, sex, cognitive test, genetic susceptibility, and the duration of follow-up in prospective studies. MetS was associated with a higher risk of mild cognitive impairment (MCI) and progression from MCI to dementia, particularly vascular dementia. Among MetS components, high blood pressure, high waist circumference, and hyperglycemia were the strongest predictors of cognitive function. MetS is associated with higher risk of cognitive impairment. Research is needed on how preventing or treating MetS affects cognition.

In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics.

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.

Metabolic syndrome and its components in relation to in vivo brain amyloid and neurodegeneration in late middle age.

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid ß (Aß) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aß or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aß burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.

Brain Amyloid Burden and Resting-State Functional Connectivity in Late Middle-Aged Hispanics.

Non-linear relations of brain amyloid beta (Aß) with task- based functional connectivity (tbFC) measured with functional magnetic resonance imaging (fMRI) have been reported in late middle age. Our objective was to examine the association between brain Aß and resting-state functional connectivity (rsFC) in late middle-aged adults. Global brain Aß burden was ascertained with 18F-Florbetaben Positron Emission Tomography (PET); rsFC was ascertained on 3T Magnetic Resonance Imaging (MRI) among 333 late middle-aged Hispanics adults without dementia in four major brain functional connectivity networks: default mode network (DMN), fronto-parietal control network (FPC), salience network (SAL) and dorsal attention network (DAN). We examined the relationship of global brain Aß with rsFC using multivariable linear regression adjusted for age, sex, education, and APOE-ε4 genotype. We quantified the non-linear associations both with quadratic terms and by categorizing Aß into three groups: low Aß, intermediate Aß, and positive Aß. We found no significant linear or non-linear associations between Aß, measured either continuously or categorically, with rsFC in the examined networks. Our null findings may be explained by the younger age of our participants in whom amyloid burden is relatively low. It is also possible that the recently reported non-linear relationship is exclusive to task fMRI and not rsfMRI.

Initial Studies with 11C-Vorozole PET Detect Overexpression of Intratumoral Aromatase in Breast Cancer.

Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor-positive breast cancer, although the response rate is just over 50% and in vitro studies suggest that only two thirds of postmenopausal breast tumors overexpress aromatase. The goal of the present study was to validate and optimize PET with 11C-vorozole for measuring aromatase expression in postmenopausal breast cancer in vivo. Methods: Ten newly diagnosed postmenopausal women with biopsy-confirmed breast cancer were administered 11C-vorozole intravenously, and PET emission data were collected between 40 and 90 min after injection. Tracer injection and scanning were repeated 2 h after ingestion of 2.5 mg of letrozole. Mean and maximal SUVs and ratios to nontumor tissue in the contralateral breast were determined at baseline and after letrozole. Biopsy specimens from the same tumors were stained for aromatase using immunohistochemistry and evaluated for stain intensity and the percentage of immune-positive cells. Results: Seven of the 10 women (70%) demonstrated increased mean focal uptake of tracer (SUV ratio > 1.1) coinciding with the mammographic location of the lesion, whereas the other 3 women (30%) did not (SUV ratio ≤ 1.0). All patients with an SUV ratio above 1.1 had mean SUVs above 2.4, and there was no overlap (SUV ratio ≤ 1; SUVmean, 0.8-1.8). The SUV ratio relative to breast around tumor was indistinguishable from the ratio to contralateral breast. Pretreatment with letrozole reduced tracer uptake in most subjects, although the percentage of blocking varied across and within tumors. Tumors with a high SUV in vivo also showed a high immunohistochemical staining intensity. Conclusion: PET with 11C-vorozole is a useful technique for measuring aromatase expression in individual breast lesions, enabling noninvasive quantitative measurement of baseline and posttreatment aromatase availability in primary tumors and metastatic lesions.

A Fully Automatic Technique for Precise Localization and Quantification of Amyloid-ß PET Scans.

Spatial heterogeneity in the accumulation of amyloid-ß plaques throughout the brain during asymptomatic as well as clinical stages of Alzheimer disease calls for precise localization and quantification of this protein using PET imaging. To address this need, we have developed and evaluated a technique that quantifies the extent of amyloid-ß pathology on a millimeter-by-millimeter scale in the brain with unprecedented precision using data from PET scans. Methods: An intermodal and intrasubject registration with normalized mutual information as the cost function was used to transform all FreeSurfer neuroanatomic labels into PET image space, which were subsequently used to compute regional SUV ratio (SUVR). We have evaluated our technique using postmortem histopathologic staining data from 52 older participants as the standard-of-truth measurement. Results: Our method resulted in consistently and significantly higher SUVRs in comparison to the conventional method in almost all regions of interest. A 2-way ANOVA revealed a significant main effect of method as well as a significant interaction effect of method on the relationship between computed SUVR and histopathologic staining score. Conclusion: These findings suggest that processing the amyloid-ß PET data in subjects' native space can improve the accuracy of the computed SUVRs, as they are more closely associated with the histopathologic staining data than are the results of the conventional approach.