Adam M. Staffaroni

Data-driven regions of interest for longitudinal change in frontotemporal lobar degeneration

Current research is investigating the potential utility of longitudinal measurement of brain structure as a marker of drug effect in clinical trials for neurodegenerative disease. Recent studies in Alzheimers disease (AD) have shown that measurement of change in empirically derived regions of interest (ROIs) allows more reliable measurement of change over time compared with regions chosen a-priori based on known effects of AD on brain anatomy. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify an empirical ROI that maximizes the effect size for the annual rate of brain atrophy in FTLD compared with healthy age matched controls, and to estimate the effect size and associated power estimates for a theoretical study that would use change within this ROI as an outcome measure. Eighty six patients with FTLD were studied, including 43 who were imaged twice at 1.5 T and 43 at 3 T, along with 105 controls (37 imaged at 1.5 T and 67 at 3 T). Empirically-derived maps of change were generated separately for each field strength and included the bilateral insula, dorsolateral, medial and orbital frontal, basal ganglia and lateral and inferior temporal regions. The extent of regions included in the 3 T map was larger than that in the 1.5 T map. At both field strengths, the effect sizes for imaging were larger than for any clinical measures. At 3 T, the effect size for longitudinal change measured within the empirically derived ROI was larger than the effect sizes derived from frontal lobe, temporal lobe or whole brain ROIs. The effect size derived from the data-driven 1.5 T map was smaller than at 3 T, and was not larger than the effect size derived from a-priori ROIs. It was estimated that measurement of longitudinal change using 1.5 T MR systems requires approximately a 3-fold increase in sample size to obtain effect sizes equivalent to those seen at 3 T. While the results should be confirmed in additional datasets, these results indicate that empirically derived ROIs can reduce the number of subjects needed for a longitudinal study of drug effects in FTLD compared with a-priori ROIs. Field strength may have a significant impact on the utility of imaging for measuring longitudinal change.

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies as a Function of Age and is Associated with Changes in Episodic Memory and Processing Speed

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimers pathology. Little is known, however, about the longitudinal trajectory of this networks intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49–87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50–66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults. SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

CapMan: independent investigation of capacity and manipulation with a new working memory paradigm

In a new working memory paradigm, CapMan, we independently investigated brain activity associated with capacity and manipulation of information. The investigation of Capacity, resulted in activation of the fronto-parietal network of regions that overlapped with areas usually found to be active in working memory tasks. The investigation of Manipulation revealed a more dorsal network of areas that also overlapped with areas usually found to be active in working memory tasks, but that did not overlap with the areas associated with Capacity. The CapMan paradigm thus appears to be able to separate the processes associated with capacity and manipulation increases and promises to be a valuable addition to the tools available for the study of working memory.

Longitudinal white matter change in frontotemporal dementia subtypes and sporadic late onset Alzheimer's disease

Background Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD. Objective To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI). Methods 60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%). Results All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups. Conclusions All three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

Data-driven regions of interest for longitudinal change in three variants of frontotemporal lobar degeneration

Longitudinal imaging of neurodegenerative disorders is a potentially powerful biomarker for use in clinical trials. In Alzheimers disease, studies have demonstrated that empirically derived regions of interest (ROIs) can provide more reliable measurement of disease progression compared with anatomically defined ROIs.

Four- and five-factor models of the WAIS-IV in a clinical sample: Variations in indicator configuration and factor correlational structure.

A growing body of research supports the validity of 5-factor models for interpreting the Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV). The majority of these studies have utilized the WAIS-IV normative or clinical sample, the latter of which differs in its diagnostic composition from the referrals seen at outpatient neuropsychology clinics. To address this concern, 2 related studies were conducted on a sample of 322 American military Veterans who were referred for outpatient neuropsychological assessment. In Study 1, 4 hierarchical models with varying indicator configurations were evaluated: 3 extant 5-factor models from the literature and the traditional 4-factor model. In Study 2, we evaluated 3 variations in correlation structure in the models from Study 1: indirect hierarchical (i.e., higher-order g), bifactor (direct hierarchical), and oblique models. The results from Study 1 suggested that both 4- and 5-factor models showed acceptable fit. The results from Study 2 showed that bifactor and oblique models offer improved fit over the typically specified indirect hierarchical model, and the oblique models outperformed the orthogonal bifactor models. An exploratory analysis found improved fit when bifactor models were specified with oblique rather than orthogonal latent factors.

A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence?

Background Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single‐molecule immunosorbent assays (Simoa) by Quanterix. Methods 57 community‐dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL‐10, IP‐10, IL‐6, TNF&agr;, and IL‐1&bgr; on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV) < 20% and outliers 3 interquartiles above the median removed), intra‐assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. Results The proportion of cytokines reliably measured on HPE (87.7–93.0%) and Simoa (75.4–93.0%) did not differ (ps > 0.32), with the exception of IL‐1&bgr; which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL‐10, IL‐6, and TNF&agr; (ps < 0.05). HPE and Simoa shared only small‐to‐moderate proportions of variance with one another on the same cytokine proteins (range: r = 0.26 for IL‐10 to r = 0.64 for IL‐6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up‐ and down‐regulation across HPE and Simoa, though still significantly differed (ps < 0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL‐6 and TNF&agr;), though with several notable exceptions for IP‐10 and IL‐10. Conclusions HPE and Simoa showed comparable detectability and intra‐assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL‐1&bgr; which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations. HighlightsMSD HPE and Quanterix Simoa are analytic platforms to detect biofluid cytokines.Detectability and reliability of the same cytokines did not differ across platforms.Absolute cytokine concentrations were higher using Simoa vs. HPE.Cross‐platform correlations were low, but cytokine ratios showed similar patterns.Cytokine measurement is platform‐specific and is best interpreted in relative terms.

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

The prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42 was examined in frontotemporal dementia subtypes.

Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults

OBJECTIVES Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

ENDOTHELIAL-DERIVED EXOSOME BIOMARKERS SUGGEST ACTIVATION OF INNATE IMMUNITY IN SUBCLINICAL CEREBROVASCULAR DISEASE

P2-245 ENDOTHELIAL-DERIVED EXOSOME BIOMARKERS SUGGESTACTIVATION OF INNATE IMMUNITY IN SUBCLINICAL CEREBROVASCULAR DISEASE Fanny Elahi, Marie Altendahl, Teresa J. Filshtein, Kaitlin Casaletto, Adam M. Staffaroni, Wilfredo Rivera Contreras, Anna M. Karydas, Yann Cobigo, Evan Fletcher, Baljeet Singh, Oliver Martinez, Howard J. Rosen, Jason Hinman, Katerina Akassoglou, Maria Glymour, Charlie S. DeCarli, Edward J. Goetzl, Joel H. Kramer, University of California San Francisco, San Francisco, CA, USA; University of California, Davis, Davis, CA, USA; Memory and Aging Center, UCSFWeill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; University of California, San Francisco, San Francisco, CA, USA; University of California at Davis, Davis, CA, USA; University of California Los Angeles, Los Angeles, CA, USA; University of California San Francisco, San Francisco, CA, USA; University of California San Francisco (UCSF), San Francisco, CA, USA. Contact e-mail: fanny.elahi@ucsf.edu