Search

Non-human primate (NHP) models are essential for developing and translating new treatments that target neural circuit dysfunction underlying human psychopathology. As a proof-of-concept for treating neuropsychiatric disorders, we used a NHP model of pathological anxiety to investigate the feasibility of decreasing anxiety by chemogenetically (DREADDs [designer receptors exclusively activated by designer drugs]) reducing amygdala neuronal activity. Intraoperative MRI surgery was used to infect dorsal amygdala neurons with AAV5-hSyn-HA-hM4Di in young rhesus monkeys. In vivo microPET studies with [11C]-deschloroclozapine and postmortem autoradiography with [3H]-clozapine demonstrated selective hM4Di binding in the amygdala, and neuronal expression of hM4Di was confirmed with immunohistochemistry. Additionally, because of its high affinity for DREADDs, and its approved use in humans, we developed an individualized, low-dose clozapine administration strategy to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in hM4Di-expressing monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology.

Background: Synaptic dysfunction occurs prior to neuronal loss in the early stages of AD. A biomarker reflective of these changes could indicate AD before clinical manifestations. SNAP‐25 is a potential candidate, but the relationship between SNAP‐25 and established AD biomarkers is unclear. Further investigation is needed to determine the utility of this biomarker during the pre‐clinical phase. Method: SNAP‐25 was measured using the Quanterix Single molecule array platform. A partial validation was conducted to evaluate assay performance in CSF and EDTA plasma. A cross‐sectional pilot study was then performed by measuring SNAP‐25 in CSF from 54 participants in the Wisconsin Registry for Alzheimer's Prevention (WRAP) and Wisconsin Alzheimer's Disease Research Center (WI‐ADRC) cohorts. SV2A synaptic density was measured in each participant using [11C]‐UCB‐J‐PET. Amyloid and tau status was determined in a subset of the group using [11C]‐PiB (N = 52) and [18F]‐MK6240‐PET (N = 44), respectively. Additional CSF biomarkers (Aß42, pTau‐181, and tTau) were measured using the Roche Cobas e601 Elecsys platform. A confirmatory study was performed with 80 additional WRAP and WI‐ADRC participants (53A+, 27 A‐). These participants did not have [11C]‐UCB‐J‐PET imaging. Result: The SNAP‐25 assay demonstrated excellent precision (<5% CV), recovery (96‐101%), and linearity in CSF. Plasma SNAP‐25 levels were detectable but inconsistent, suggesting matrix interference. In the pilot study, SNAP‐25 was highly correlated with CSF pTau‐181 and tTau (Figures 1A, 1B). SNAP‐25 was not correlated with CSF Aß42 (Figure 1C). A modest but significant correlation was observed with amyloid PET in the pilot study (Figure 2A) but not in the confirmatory study (Figure 3). SNAP‐25 did not correlate with SV2A density (Figure 2B) or fibrillary tau (Figure 2A). Mean SNAP‐25 levels were significantly different between amyloid‐ and tau‐positive groups compared to biomarker negative controls (p < 0.001 for amyloid, p < 0.05 for tau). Similar trends were observed in the confirmatory study (Figure 3). Conclusion: These results demonstrate a close relationship between SNAP‐25 and soluble tau in CSF, suggesting that CSF SNAP‐25 reflects early Aß‐induced neuronal impairment in a way that correlates with tau pathophysiology. This indicates that SNAP‐25 could be a useful biomarker of early neurodegeneration in pre‐clinical AD. [ABSTRACT FROM AUTHOR]

Background: Neuronal hypometabolism measured with [18F]FDG PET scans can be used to identify neurodegeneration as part of the AT(N) (amyloid, tau, neurodegeneration) framework in AD. PET imaging of synaptic vesicle glycoprotein SV2A using [11C]UCB‐J provides an index of synaptic density, which has been shown to decrease during neurodegeneration. The purpose of this study was to examine the regional relationship between neuronal metabolism and synaptic density in participants across the continuum of AD‐related pathology. Method: Participants were recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer's Prevention (WRAP) study. A subset of 13 participants (Table 1) were selected who had completed cognitive testing, structural MR imaging, and PET imaging with the following: [11C]PiB centiloid (CL) for amyloid +/‐ status, [18F]MK‐6240 SUVR for tau +/‐ status, [11C]UCB‐J DVR for regional synaptic density burden, and [18F]FDG SUVR for regional glucose metabolism. UCB‐J and FDG analysis used a whole cerebellum reference region; PiB and MK‐6240 analysis used cerebellar GM reference regions. Inter‐tracer (UCB‐J/FDG) correlations were performed in Freesurfer‐defined bilateral Braak‐associated ROIs (Medial Temporal Lobe [MTL]: entorhinal cortex, hippocampus, and amygdala; Ventral Temporal Lobe [VTL]: fusiform, lingual, and inferior temporal gyri), signature regions of hypometabolism in AD (posterior cingulate, parietal, and frontal cortices) and a region with only marginal hypometabolism in AD (occipital cortex). Associations were determined using Pearson correlations (r). Result: All ROIs demonstrate a positive association between FDG SUVR and UCB‐J DVR, with r > 0.7 and p < 0.01 (Figure 1). The occipital, frontal, and posterior cingulate cortices demonstrate the strongest correlations (r = 0.84, 0.83, and 0.81, respectively). Conclusion: In cognitively impaired and unimpaired participants showing varying degrees of β‐amyloid and neurofibrillary tau burden, strong positive correlations are observed in regions associated with AD tau pathology and hypometabolism. Correlations are also observed in regions not typically associated with hypometabolism. This suggests that a relationship may exist between synaptic density and neuronal metabolism in the presence of AD neuropathology. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is characterized by earlier beta‐amyloid (Aβ) plaque accumulation and an increased prevalence of Alzheimer's disease (AD) due to trisomy 21 and triplication of the amyloid precursor protein (APP) gene. While the age of AD onset is earlier in DS, AD pathology progression in non‐DS populations follows similar trends to the DS cohort. This study compares the accumulation rate of Aβ between DS and non‐DS populations measured with [C‐11]PiB at same site using the same scanning procedures. Methods: Individuals with at least one Aβ+ [C‐11]PiB scan (Global SUVR>1.40), and at least one Aβ‐ scan from our site at the University of Wisconsin were selected for this study. 12 out of 58 DS participants in the Neurodegeneration in Aging DS (NiAD) study and 14 out of 246 non‐DS subjects from the PREDICT study fit this criteria. All images were collected on an ECAT HR+ scanner from 50‐70 minutes injection (i.d. = 15mCi). Reconstructed PET images were aligned and summed before being normalized into MNI‐152 space and converted into an SUVR image using cerebellar grey matter as a reference region. We determined rate of Aβ accumulation as the change in global SUVR per year, defined as the average of grey matter regions in the anterior cingulate, frontal cortex, parietal cortex, precuneus, temporal cortex, and striatum, and focused on the period when participants became Aβ+. Results: Plotting global [C‐11]PiB SUVR and age (Fig 1) there is no age overlap between the two groups. The average rate of amyloid accumulation per year when becoming Aβ+ in the DS group was 0.058±0.026 compared to 0.059±0.028 for the non‐DS sample. The two groups have notably similar mean values, although when organized into box plots (Fig 2), the interquartile range of the DS subjects is 0.044 compared to a tighter 0.019 for non‐DS. Conclusions: The pattern of Aβ accumulation in DS and non‐DS groups becoming Aβ+ have similar distributions. While we might expect a higher rate in the DS population due to the additional APP gene, our findings do not support this hypothesis. However, considerable variability in the rate of accumulation is observed requiring further investigation towards understanding this process. [ABSTRACT FROM AUTHOR]

Background: PET amyloid [11C]PiB imaging has revealed early detection of Ab in the striatum in individuals with Down Syndrome (DS), a group carrying genetic risk for AD. The goal of this investigation is to examine striatal binding of [11C]PiB and [18F]florbetapir (FBP) to determine if similar striatal uptake profiles are observed in individuals with DS. Methods: PET scans were acquired as part of the Alzheimer's Biomarker Consortium – Down Syndrome (ABC‐DS) study. DS participants were scanned with either PiB (n=204; ages 25‐56 yrs) or FBP (n=84; ages 40‐85 yrs) at seven academic sites. SUVR images were created with acquisition times of 50‐70min for both radiotracers, using a cerebellar reference region. ROIs were defined for the anterior ventral striatum (AVS) and the full cortex (CTX). SUVR was then converted to centiloids (CL) using published methods (Klunk 2015) with DS‐specific modifications, including AVS extraction and approximate CL_AVS. Aβ(+) was defined using a threshold of 18.1 CL in CTX ROI, categorizing Aβ(‐) and Aβ(+) groups. Comparisons across PiB and FBP examined 1) the proportion of CL_AVS values exceeding the threshold in the Aβ(‐) group and 2) the difference between SUVR_AVS and SUVR_CTX in the Aβ(+) group. Results: 58/204 subjects (PiB) and 72/84 subjects (FBP) were Aβ(+), with differences in Aβ(+) presumably due to greater age and advanced neurodegeneration in the FBP group. For the Aβ(‐) comparison, elevated CL_AVS was detected in 16/146 (PiB) and 0/12 (FBP). The average CL_AVS of those that exceeded the threshold was 37.0±12.7 CL (PiB) (mean±SD). For the Aβ(+) comparison, 52/58 (PiB) and 52/72 (FBP) had CL_AVS greater than their CL_CTX. The average difference between SUVR_AVS and SUVR_CTX for the Aβ(+) group was 0.50±0.39 SUVR (46.9±36.8 CL) (PiB) and 0.08±0.18 SUVR (14.2±31.0 CL) (FBP). Conclusions: PiB PET exhibited higher uptake in the striatum during early stages of amyloid deposition. PiB revealed a 6x greater difference than FBP between striatal to cortical SUVR in the Aβ(+) group. Neuropathological investigation is ongoing to characterize these differences in striatal binding in DS. Despite this difference in early‐stage binding, both PiB and FBP demonstrate sensitivity for determining the presence of Aβ in DS. [ABSTRACT FROM AUTHOR]

[ 11 C]ER176 is a next generation PET radioligand for imaging 18 kDa translocator protein, a biomarker for neuroinflammation. The goal of this work was to investigate alternative strategies for the radiochemical synthesis, purification, and formulation of [ 11 C]ER176. An optimized tri-solvent high-performance liquid chromatography (HPLC) protocol is described to separate the hydro-de-chlorinated byproduct from [ 11 C]ER176. A newly implemented solid phase extraction work-up efficiently removed HPLC solvent while maintaining chemical purity and overall radiochemical yield and purity. This new HPLC purification and final formulation was completed within 40 min, providing 2.7 ± 0.5 GBq of [ 11 C]ER176 at end of synthesis with 1400 ± 300 GBq/μmol molar activity while meeting all specifications for radiopharmaceutical quality control tests for human research use., (Copyright © 2021. Published by Elsevier Ltd.)