IMPORTANCE Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. OBJECTIVE To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11 C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11 C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. MAIN OUTCOMES AND MEASURES Outcomes were 11 C-UCB-J-specific binding (binding potential [BP ND ]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. RESULTS Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11 C-UCB-J-PET BP ND (cognitively normal participants: mean [SD] BP ND , 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BP ND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11 C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and r...

Charcoal is found in water, soil, and sediment where it may act as a sorbent of organic pollutants. The sorption of organic compounds to natural solids often shows hysteresis. The purpose of this study was to determine the source of pronounced hysteresis that we found in the sorption of a hydrophobic compound (benzene) in water to a maple-wood charcoal prepared by oxygen-limited pyrolysis at 673 K. Gas adsorption (N2, Ar, CO2), 13C NMR, and FTIR show the charcoal to be a microporous solid composed primarily of elemental (aromatic) C and secondarily of carboxyl and phenolic C. Nonlocal density functional theory (N2, Ar) and Monte Carlo (CO2) calculations reveal a porosity of 0.15 cm3/g, specific surface area of 400 m2/g, and appreciable porosity in ultramicropores < 10 A. Benzene sorption-desorption conditions were chosen to eliminate artificial causes of hysteresis (rate-limiting diffusion, degradation, colloids effect). Charcoal sorbed up to its own weight of benzene at approximately 69% of benzene water solubility. Sorption was highly irreversible over most of the range tested (10(-4)-10(3) microg/mL). A dimensionless irreversibility index (/i) (0 < or = /i < or = 1) based on local slopes of adsorption and desorption branches was evaluated at numerous places along the isotherm. /i decreases as C increases, from 0.9-1 at low concentration to approximately 0 (approximately fully reversible) at the highest concentrations. Using sedimentation and volumetric displacement measurements, benzene is observed to cause pronounced swelling (up to > 2-fold) of the charcoal particles. It is proposed that hysteresis is due to pore deformation by the solute, which results in the pathway of sorption being different than the pathway of desorption and which leads to entrapment of some adsorbate as the polyaromatic scaffold collapses during desorption. It is suggested that intra-charcoal mass transport may be influenced by structural rearrangement of the solid, in addition to molecular diffusion.

Hysteresis, or isotherm nonsingularity, is a confounding issue in sorption research that undermines the commonplace assumption of reversibility in environmental fate and effects models for organic compounds in soil media. Until now, a molecular-level mechanism for true hysteresis when the sorbate is retrievable, structurally intact, has not been forthcoming. We show here that two organic soils exhibit the "conditioning effect", which refers to the enhancement in sorption of a compound following brief exposure of the sorbent to high concentrations of the same or a similar compound. The conditioning effect has been used in support of a pore deformation mechanism for hysteresis in glassy polymers. By this mechanism, the sorbate causes irreversible changes in the structure of internal nanopores (holes) in the organic matrix upon its sorption. Trichloromethane was the test solute for dichloromethane-conditioned Pahokee soil (44.6% organic carbon), and chlorobenzene and 1,2,4-trichlorobenzene were the test solutes for benzene-conditioned Mount Pleasant silt loam (4.5% organic carbon). In each case, the isotherm of the test solute in the conditioned soil was shifted upward of, and was less linear than, the corresponding isotherm in the nonconditioned control. Application of the polymer-based Dual-Mode (partitioning-hole filling) Model shows an expansion of the hole domain as a result of conditioning. The memory of the conditioning effect persists for longer than 96 days at 21 degrees C but is lost upon heating the sample at 100 degrees C. A three-step (sorption-desorption-resorption) experiment demonstrated hysteresis followed by enhanced resorption, implying a mechanistic relationship between hysteresis and the conditioning effect. The results indicate that irreversible pore deformation is a mechanism for hysteresis in natural organic matter materials and suggest that slow matrix relaxation may contribute to the often-observed long-term resistance of some contaminants to desorption.

Sorption of organic chemicals to soils and sediments often shows true hysteresis (i.e., nonsingularity of the sorption-desorption isotherm not attributable to known experimental artifacts). Since true sorption hysteresis is fundamentally important to contaminant fate, a way to quantify it is desirable. Previously proposed indices of hysteresis are empirical and usually depend on the isotherm model. True sorption hysteresis to synthetic and natural organic solids has been attributed to irreversible alteration of the solid during the sorption-desorption cycle. Given this mechanism, we propose the Thermodynamic Index of Irreversibility (TII) for quantifying hysteresis in soils where natural organic matter dominates the sorption process. The TII is based on the difference in free energy between the real desorption state and the hypothetical fully reversible state. The index is 0 for completely reversible systems and approaches 1 as the process tends toward complete irreversibility. It does not require any assumptions about the physical properties or molecular composition of the solid, and it does not depend on a specific equilibrium model. A sensitivity analysis of measurement errors provides general recommendations for the setup of sorption-desorption experiments. The TII was applied to sorption of 1,4-dichlorobenzene (DCB) to two high-organic soils, Pahokee peat (PP) and Amherst soil (AS), and a low-rank coal reference material, Beulah-Zap lignite (BZL). Common artificial causes of hysteresis were eliminated. Hysteresis was significant in the peat and the coal. The TII was clearly concentration dependent for both solids; it decreased with concentration for the peat, but increased with concentration for the coal. The TII allows quantification of hysteresis as a function of sorbate-sorbent combination, concentration, time, and other variables.