Loss of cholinergic input to the entorhinal cortex is an early indicator of cognitive impairment in natural aging of humans and mice.

In a series of translational experiments using fully quantitative positron emission tomography (PET) imaging with a new tracer specific for the vesicular acetylcholine transporter ([18F]VAT) in vivo in humans, and genetically targeted cholinergic markers in mice, we evaluated whether changes to the cholinergic system were an early feature of age-related cognitive decline. We found that deficits in cholinergic innervation of the entorhinal cortex (EC) and decline in performance on behavioral tasks engaging the EC are, strikingly, early features of the aging process. In human studies, we recruited older adult volunteers that were physically healthy and without prior clinical diagnosis of cognitive impairment. Using [18F]VAT PET imaging, we demonstrate that there is measurable loss of cholinergic inputs to the EC that can serve as an early signature of decline in EC cognitive performance. These deficits are specific to the cholinergic circuit between the medial septum and vertical limb of the diagonal band (MS/vDB; CH1/2) to the EC. Using diffusion imaging, we further demonstrate impaired structural connectivity in the tracts between the MS/vDB and EC in older adults with mild cognitive impairment. Experiments in mouse, designed to parallel and extend upon the human studies, used high resolution imaging to evaluate cholinergic terminal density and immediate early gene (IEG) activity of EC neurons in healthy aging mice and in mice with genetic susceptibility to accelerated accumulation amyloid beta plaques and hyperphosphorylated mouse tau. Across species and aging conditions, we find that the integrity of cholinergic projections to the EC directly correlates with the extent of EC activation and with performance on EC-related object recognition memory tasks. Silencing EC-projecting cholinergic neurons in young, healthy mice during the object-location memory task impairs object recognition performance, mimicking aging. Taken together we identify a role for acetylcholine in normal EC function and establish loss of cholinergic input to the EC as an early, conserved feature of age-related cognitive decline in both humans and rodents.

Measuring brain glucose metabolism in order to predict response to antidepressant or placebo: A randomized clinical trial.

There is critical need for a clinically useful tool to predict antidepressant treatment outcome in major depressive disorder (MDD) to reduce suffering and mortality. This analysis sought to build upon previously reported antidepressant treatment efficacy prediction from 2-[18F]-fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) using metabolic rate of glucose uptake (MRGlu) from dynamic FDG-PET imaging with the goal of translation to clinical utility. This investigation is a randomized, double-blind placebo-controlled trial. All participants were diagnosed with MDD and received an FDG-PET scan before randomization and after treatment. Hamilton Depression Rating Scale (HDRS-17) was completed in participants diagnosed with MDD before and after 8 weeks of escitalopram, or placebo. MRGlu (mg/(min*100 ml)) was estimated within the raphe nuclei, right insula, and left ventral Prefrontal Cortex in 63 individuals. Linear regression was used to examine the association between pretreatment MRGlu and percent decrease in HDRS-17. Additionally, the association between percent decrease in HDRS-17 and percent change in MRGlu between pretreatment scan and post-treatment scan was examined. Covariates were treatment type (SSRI/placebo), handedness, sex, and age. Depression severity decrease (n = 63) was not significantly associated with pretreatment MRGlu in the raphe nuclei (ß = -2.61e-03 [-0.26, 0.25], p = 0.98), right insula (ß = 0.05 [-0.23, 0.32], p = 0.72), or ventral prefrontal cortex (ß = 0.06 [-0.23, 0.34], p = 0.68) where ß is the standardized estimated coefficient, with a 95% confidence interval, or in whole brain voxelwise analysis (family-wise error correction, alpha = 0.05). MRGlu percent change was not significantly associated with depression severity decrease (n = 58) before multiple comparison correction in the RN (ß = 0.20 [-0.07, 0.47], p = 0.15), right insula (ß = 0.24 [-0.03, 0.51], p = 0.08), or vPFC (ß = 0.22 [-0.06, 0.50], p = 0.12). We propose that FDG-PET imaging does not indicate a clinically relevant biomarker of escitalopram or placebo treatment response in heterogeneous major depressive disorder cohorts. Future directions include focusing on potential biologically-based subtypes of major depressive disorder by implementing biomarker stratified designs.

Neuroinflammation in World Trade Center responders at midlife: A pilot study using [18F]-FEPPA PET imaging.

BACKGROUND: Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. OBJECTIVES: Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. METHODS: Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [18F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [18F]-FEPPA total distribution volumes as the outcomes. RESULT: Responders were 56.0 â€‹± â€‹4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [18F]-FEPPA binding predominantly in the hippocampus (d â€‹= â€‹0.72, P â€‹= â€‹0.001) and frontal cortex (d â€‹= â€‹0.64, P â€‹= â€‹0.004). Longer exposure duration to WTC sites was associated with higher [18F]-FEPPA binding in the parietal cortex. CONCLUSION: Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders.

Selective hippocampal subfield volume reductions in World Trade Center responders with cognitive impairment.

INTRODUCTION: The objective of this study was to investigate associations between dementia in World Trade Center (WTC) responders and in vivo volumetric measures of hippocampal subfield volumes in WTC responders at midlife. METHODS: A sample of 99 WTC responders was divided into dementia and unimpaired groups. Participants underwent structural T1-weighted magnetic resonance imaging. Volumetric measures included the overall hippocampus and eight subfields. Regression models examined volumetric measure of interest adjusting for confounders including intracranial volume. RESULTS: Dementia was associated with smaller hippocampal volume and with reductions across hippocampal subfields. Smaller hippocampal subfield volumes were associated with longer cumulative time worked at the WTC. Domain-specific cognitive performance was associated with lower volumetric measures across hippocampal subregions. CONCLUSIONS: This is the first study to investigate hippocampal subfield volumes in a sample of WTC responders at midlife. Selective hippocampal subfield volume reductions suggested abnormal cognition that were associated with WTC exposure duration.