Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Background: Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Pulsatility analysis of the circle of Willis.

Purpose: To evaluate the phenomenological significance of cerebral blood pulsatility imaging in aging research. Methods: N = 38 subjects from 20 to 72 years of age (24 females) were imaged with ultrafast MRI with a sampling rate of 100 ms and simultaneous acquisition of pulse oximetry data. Of these, 28 subjects had acceptable MRI and pulse data, with 16 subjects between 20 and 28 years of age, and 12 subjects between 61 and 72 years of age. Pulse amplitude in the circle of Willis was assessed with the recently developed method of analytic phase projection to extract blood volume waveforms. Results: Arteries in the circle of Willis showed pulsatility in the MRI for both the young and old age groups. Pulse amplitude in the circle of Willis significantly increased with age (p = 0.01) but was independent of gender, heart rate, and head motion during MRI. Discussion and conclusion: Increased pulse wave amplitude in the circle of Willis in the elderly suggests a phenomenological significance of cerebral blood pulsatility imaging in aging research. The physiologic origin of increased pulse amplitude (increased pulse pressure vs. change in arterial morphology vs. re-shaping of pulse waveforms caused by the heart, and possible interaction with cerebrospinal fluid pulsatility) requires further investigation.

In vivo tau is associated with change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels (18F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-ß pathology.

Distinct and joint effects of low and high levels of Aß and tau deposition on cortical thickness.

Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment.

BACKGROUND: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI). METHODS: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT). RESULTS: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%. DISCUSSION: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

Positron Emission Tomography reveals age-associated hypothalamic microglial activation in women.

In rodents, hypothalamic inflammation plays a critical role in aging and age-related diseases. Hypothalamic inflammation has not previously been assessed in vivo in humans. We used Positron Emission Tomography (PET) with a radiotracer sensitive to the translocator protein (TSPO) expressed by activated microglia, to assess correlations between age and regional brain TSPO in a group of healthy subjects (n = 43, 19 female, aged 23-78), focusing on hypothalamus. We found robust age-correlated TSPO expression in thalamus but not hypothalamus in the combined group of women and men. This pattern differs from what has been described in rodents. Prominent age-correlated TSPO expression in thalamus in humans, but in hypothalamus in rodents, could reflect evolutionary changes in size and function of thalamus versus hypothalamus, and may be relevant to the appropriateness of using rodents to model human aging. When examining TSPO PET results in women and men separately, we found that only women showed age-correlated hypothalamic TSPO expression. We suggest this novel result is relevant to understanding a stark sex difference in human aging: that only women undergo loss of fertility-menopause-at mid-life. Our finding of age-correlated hypothalamic inflammation in women could have implications for understanding and perhaps altering reproductive aging in women.

Evidence suggesting common mechanisms underlie contralateral and ipsilateral negative BOLD responses in the human visual cortex.

The task-evoked positive BOLD response (PBR) to a unilateral visual hemi-field stimulation is often accompanied by robust and sustained contralateral as well as ipsilateral negative BOLD responses (NBRs) in the visual cortex. The signal characteristics and the neural and/or vascular mechanisms that underlie these two types of NBRs are not completely understood. In this paper, we investigated the properties of these two types of NBRs. We first demonstrated the linearity of both NBRs with respect to stimulus duration. Next, we showed that the hemodynamic response functions (HRFs) of the two NBRs were similar to each other, but significantly different from that of the PBR. Moreover, the subject-wise expressions of the two NBRs were tightly coupled to the degree that the correlation between the two NBRs was significantly higher than the correlation between each NBR and the PBR. However, the activation patterns of the two NBRs did not show a high level of interhemispheric spatial similarity, and the functional connectivity between them was not different than the interhemispheric functional connectivity between the NBRs and PBR. Finally, while attention did modulate both NBRs, the attention-related changes in their HRFs were similar. Our findings suggest that the two NBRs might be generated through common neural and/or vascular mechanisms involving distal/deep brain regions that project to the two hemispheres.

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.

Landmark-guided region-based spatial normalization for functional magnetic resonance imaging.

As the size of the neuroimaging cohorts being increased to address key questions in the field of cognitive neuroscience, cognitive aging, and neurodegenerative diseases, the accuracy of the spatial normalization as an essential preprocessing step becomes extremely important. Existing spatial normalization methods have poor accuracy particularly when dealing with the highly convoluted human cerebral cortex and when brain morphology is severely altered (e.g., aging populations). To address this shortcoming, we propose a novel spatial normalization technique that takes advantage of the existing surface-based human brain parcellation to automatically identify and match regional landmarks. To simplify the nonlinear whole brain registration, the identified landmarks of each region and its counterpart are registered independently with topology-preserving deformation. Next, the regional warping fields are combined by an inverse distance weighted interpolation technique to have a global warping field for the whole brain. To ensure that the final warping field is topology-preserving, we used simultaneously forward and reverse maps with certain symmetric constraints to yield bijectivity. We have evaluated our proposed solution using both simulated and real (structural and functional) human brain images. Our evaluation shows that our solution can enhance structural correspondence compared to the existing methods. Such improvement also increases the sensitivity and specificity of the functional imaging studies, reducing the required number of subjects and subsequent study costs. We conclude that our proposed solution can effectively substitute existing substandard spatial normalization methods to deal with the demand of large cohorts which is now common in clinical and aging studies.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.

Topographical Overlapping of the Amyloid-ß and Tau Pathologies in the Default Mode Network Predicts Alzheimer's Disease with Higher Specificity.

BACKGROUND: While amyloid-ß (Aß) plaques and tau tangles are the well-recognized pathologies of Alzheimer's disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. OBJECTIVE: We hypothesize and provide preliminary evidence that topographically overlapping Aß and tau within the default mode network (DMN) play more critical roles in the underlying pathophysiology of AD than each of the tau and/or Aß pathologies alone. METHODS: We used our newly developed quantification methods and publicly available neuroimaging data from 303 individuals to provide preliminary evidence of our hypothesis. RESULTS: We first showed that the probability of observing overlapping Aß and tau is significantly higher within than outside the DMN. We then showed evidence that using Aß and tau overlap can increase the reliability of the prediction of healthy individuals converting to mild cognitive impairment (MCI) and to a lesser degree converting from MCI to AD. Finally, we provided evidence that while the initial accumulations of Aß and tau seems to be started independently in the healthy participants, the accumulations of the two pathologies interact in the MCI and AD groups. CONCLUSION: These findings shed some light on the complex pathophysiology of AD and suggest that overlapping Aß and tau pathologies within the DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease.

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.

Predictive utility of task-related functional connectivity vs. voxel activation.

Functional connectivity, both in resting state and task performance, has steadily increased its share of neuroimaging research effort in the last 1.5 decades. In the current study, we investigated the predictive utility regarding behavioral performance and task information for 240 participants, aged 20-77, for both voxel activation and functional connectivity in 12 cognitive tasks, belonging to 4 cognitive reference domains (Episodic Memory, Fluid Reasoning, Perceptual Speed, and Vocabulary). We also added a model only comprising brain-structure information not specifically acquired during performance of a cognitive task. We used a simple brain-behavioral prediction technique based on Principal Component Analysis (PCA) and regression and studied the utility of both modalities in quasi out-of-sample predictions, using split-sample simulations (= 5-fold Monte Carlo cross validation) with 1,000 iterations for which a regression model predicting a cognitive outcome was estimated in a training sample, with a subsequent assessment of prediction success in a non-overlapping test sample. The sample assignments were identical for functional connectivity, voxel activation, and brain structure, enabling apples-to-apples comparisons of predictive utility. All 3 models that were investigated included the demographic covariates age, gender, and years of education. A minimal reference model using simple linear regression with just these 3 covariates was included for comparison as well and was evaluated with the same resampling scheme as described above. Results of the comparison between voxel activation and functional connectivity were mixed and showed some dependency on cognitive outcome; however, mean differences in predictive utility between voxel activation and functional connectivity were rather small in terms of within-modality variability or predictive success. More notably, only in the case of Fluid Reasoning did concurrent functional neuroimaging provided compelling about cognitive performance beyond structural brain imaging or the minimal reference model.

Attenuation of motion artifacts in fMRI using discrete reconstruction of irregular fMRI trajectories (DRIFT).

PURPOSE: Numerous studies report motion as the most detrimental source of noise and artifacts in fMRI. Current motion correction methods fail to completely address the motion problem. Retrospective techniques such as spatial realignment can correct for between-volume misalignment but fail to address within volume contamination and spin-history artifacts. Prospective motion correction can prevent spin-history artifacts but currently cannot update the gradients fast enough to remove k-space filling artifacts, calling for a hybrid approach to fully address these problems. THEORY AND METHODS: Motion can be mathematically formulated into the MR signal equation to describe the motion artifacts at their origin in k-space. From these equations, it is demonstrated that different motions have different effects on the signal. A novel motion correction algorithm is designed from these equations to remove motion-induced artifacts directly in k-space, discrete reconstruction of irregular fMRI trajectory (DRIFT). This method is evaluated rigorously using fMRI simulations and data from a rotating phantom inside the scanner. RESULTS: The results indicate that although some motion types have negligible effects on the MR signal, others produce catastrophic and lasting artifacts even after motion cessation. In simulation, DRIFT is able to remove motion artifacts in the absence of spin history. In a phantom scan, DRIFT significantly attenuates the motion artifacts in the fMRI data. CONCLUSION: Neither prospective nor retrospective motion correction methods could completely remove the motion artifacts from the fMRI data. However, DRIFT, as a retrospective technique, when combined with prospective motion correction, can eliminate a significant portion of motion artifacts.

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.

Apolipoprotein E genotype and in vivo amyloid burden in middle-aged Hispanics.

OBJECTIVE: To examine in vivo amyloid burden in relation to APOEε4 genotype in middle-aged Hispanics. We hypothesize higher amyloid levels among APOE ε4 carriers vs APOE ε4 noncarriers. METHODS: This is a cross-sectional study in a community-based sample of 249 middle-aged Hispanics in New York City who underwent a 3T brain MRI and PET with the amyloid radioligand 18F-florbetaben. APOE genotype was the primary exposure. The primary outcome was amyloid positivity. The secondary outcome was subthreshold amyloid levels examined as a continuous variable. RESULTS: APOE ε4 carriers (n = 85) had a higher frequency (15.3%) of amyloid positivity compared to APOE ε4 noncarriers (n = 164, 1.8%). In the subthreshold group of amyloid-negative participants (n = 233), APOE ε4 carriers (n = 72) had a 0.02 (95% confidence interval [CI] 0.01-0.04) higher global brain amyloid standardized uptake value ratio (SUVR) compared to APOE ε4 noncarriers (n = 161). Compared to participants with the ε3/ε3 genotype, participants with ε4/ε4 had the highest frequency of amyloid positivity (28.6%), followed by those with ε3/ε4 (11%). Among amyloid-negative participants (n = 233), compared to participants with ε3/ε3 (n = 134), those with ε4/ε4 (n = 5) had a 0.12 (95% CI 0.07-0.17) higher global brain amyloid SUVR, and those with ε3/ε4 had a 0.02 higher SUVR (95% CI 0.003-0.04). Results were similar when a median split was used for elevated amyloid, when continuous amyloid SUVR was analyzed in all participants, and in nonparametric Mann-Whitney comparisons. CONCLUSION: Middle-aged Hispanic APOE ε4 carriers have higher in vivo brain amyloid burden compared with noncarriers, as reported in non-Hispanics.