Proton Shell Gaps in N=28 Nuclei from the First Complete Spectroscopy Study with FRIB Decay Station Initiator.

The first complete measurement of the ß-decay strength distribution of _{17}^{45}Cl_{28} was performed at the Facility for Rare Isotope Beams (FRIB) with the FRIB Decay Station Initiator during the second FRIB experiment. The measurement involved the detection of neutrons and γ rays in two focal planes of the FRIB Decay Station Initiator in a single experiment for the first time. This enabled an analytical consistency in extracting the ß-decay strength distribution over the large range of excitation energies, including neutron unbound states. We observe a rapid increase in the ß-decay strength distribution above the neutron separation energy in _{18}^{45}Ar_{27}. This was interpreted to be caused by the transitioning of neutrons into protons excited across the Z=20 shell gap. The SDPF-MU interaction with reduced shell gap best reproduced the data. The measurement demonstrates a new approach that is sensitive to the proton shell gap in neutron rich nuclei according to SDPF-MU calculations.

Development of Pyridothiophene Compounds for PET Imaging of α-Synuclein.

Aggregated α-synuclein (α-syn) protein is a pathological hallmark of Parkinson's disease (PD) and Lewy body dementia (LBD). Development of positron emission tomography (PET) radiotracers to image α-syn aggregates has been a longstanding goal. This work explores the suitability of a pyridothiophene scaffold for α-syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn-44; Kd=1.85 nM) were synthesized and screened against [3H]asyn-44 in competitive binding assays using post-mortem PD brain homogenates. Equilibrium inhibition constant (Ki) values of the most potent compounds were determined, of which three had Ki's in the lower nanomolar range (12-15 nM). An autoradiography study confirmed that [3H]asyn-44 is promising for imaging brain sections from multiple system atrophy and PD donors. Fluorine-18 labelled asyn-44 was synthesized in 6±2 % radiochemical yield (decay-corrected, n=5) with a molar activity of 263±121 GBq/µmol. Preliminary PET imaging of [18F]asyn-44 in rats showed high initial brain uptake (>1.5 standardized uptake value (SUV)), moderate washout (~0.4 SUV at 60 min), and low variability. Radiometabolite analysis showed 60-80 % parent tracer in the brain after 30 and 60 mins. While [18F]asyn-44 displayed good in vitro properties and acceptable brain uptake, troublesome radiometabolites precluded further PET imaging studies. The synthesis and in vitro evaluation of additional pyridothiophene derivatives are underway, with the goal of attaining improved affinity and metabolic stability.

Characterizing the emergence of amyloid and tau burden in Down syndrome.

INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aß) trajectories were modeled to provide individual-level estimates of Aß-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. HIGHLIGHTS: Longitudinal amyloid trajectories reveal rapid Aß accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A.

Beyond monoamines: II. Novel applications for PET imaging in psychiatric disorders.

Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. For nearly 30 years, the centrality of monoamine dysfunction in psychiatric disorders drove the development of an armamentarium of monoaminergic PET radiopharmaceuticals and imaging methodologies. However, continued investments in monoamine-enhancing drug development realized only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely parallelled drug development priorities, resulting in the development of new PET imaging agents for non-monoamine targets. In part two of this review, we survey clinical research studies using the novel targets and radiotracers described in part one across major psychiatric application areas such as substance use disorders, anxiety disorders, eating disorders, personality disorders, mood disorders, and schizophrenia. Important limitations of the studies described are discussed, as well as key methodologic issues, challenges to the field, and the status of clinical trials seeking to exploit these targets for novel therapeutics.

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders.

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non-invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15 O]H2 O and [18 F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine-enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine-enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non-monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2 X7 receptor, type 1 cannabinoid receptor (CB1 ), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed.

Microsecond Isomer at the N=20 Island of Shape Inversion Observed at FRIB.

Excited-state spectroscopy from the first experiment at the Facility for Rare Isotope Beams (FRIB) is reported. A 24(2)-µs isomer was observed with the FRIB Decay Station initiator (FDSi) through a cascade of 224- and 401-keV γ rays in coincidence with ^{32}Na nuclei. This is the only known microsecond isomer (1 µs≤T_{1/2}<1 ms) in the region. This nucleus is at the heart of the N=20 island of shape inversion and is at the crossroads of the spherical shell-model, deformed shell-model, and ab initio theories. It can be represented as the coupling of a proton hole and neutron particle to ^{32}Mg, ^{32}Mg+π^{-1}+ν^{+1}. This odd-odd coupling and isomer formation provides a sensitive measure of the underlying shape degrees of freedom of ^{32}Mg, where the onset of spherical-to-deformed shape inversion begins with a low-lying deformed 2^{+} state at 885 keV and a low-lying shape-coexisting 0_{2}^{+} state at 1058 keV. We suggest two possible explanations for the 625-keV isomer in ^{32}Na: a 6^{-} spherical shape isomer that decays by E2 or a 0^{+} deformed spin isomer that decays by M2. The present results and calculations are most consistent with the latter, indicating that the low-lying states are dominated by deformation.

In Pre-Clinical AD Small Vessel Disease is Associated With Altered Hippocampal Connectivity and Atrophy.

OBJECTIVE: Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aß) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. METHODS: This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aß, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. RESULTS: We found that, in WMH (+) older adults greater Aß burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aß burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. CONCLUSION: These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aß positivity to neurodegeneration, and subsequent AD.

11C-PiB PET can underestimate brain amyloid-ß burden when cotton wool plaques are numerous.

Individuals with familial Alzheimer's disease due to PSEN1 mutations develop high cortical fibrillar amyloid-ß load but often have lower cortical 11C-Pittsburgh compound B (PiB) retention than Individuals with sporadic Alzheimer's disease. We hypothesized this is influenced by limited interactions of Pittsburgh compound B with cotton wool plaques, an amyloid-ß plaque type common in familial Alzheimer's disease but rare in sporadic Alzheimer's disease. Histological sections of frontal and temporal cortex, caudate nucleus and cerebellum were obtained from 14 cases with sporadic Alzheimer's disease, 12 cases with familial Alzheimer's disease due to PSEN1 mutations, two relatives of a PSEN1 mutation carrier but without genotype information and three non-Alzheimer's disease cases. Sections were processed immunohistochemically using amyloid-ß-targeting antibodies and the fluorescent amyloid stains cyano-PiB and X-34. Plaque load was quantified by percentage area analysis. Frozen homogenates from the same brain regions from five sporadic Alzheimer's disease and three familial Alzheimer's disease cases were analysed for 3H-PiB in vitro binding and concentrations of amyloid-ß1-40 and amyloid-ß1-42. Nine sporadic Alzheimer's disease, three familial Alzheimer's disease and three non-Alzheimer's disease participants had 11C-PiB PET with standardized uptake value ratios calculated using the cerebellum as the reference region. Cotton wool plaques were present in the neocortex of all familial Alzheimer's disease cases and one sporadic Alzheimer's disease case, in the caudate nucleus from four familial Alzheimer's disease cases, but not in the cerebellum. Cotton wool plaques immunolabelled robustly with 4G8 and amyloid-ß42 antibodies but weakly with amyloid-ß40 and amyloid-ßN3pE antibodies and had only background cyano-PiB fluorescence despite labelling with X-34. Relative to amyloid-ß plaque load, cyano-Pittsburgh compound B plaque load was similar in sporadic Alzheimer's disease while in familial Alzheimer's disease it was lower in the neocortex and the caudate nucleus. In both regions, insoluble amyloid-ß1-42 and amyloid-ß1-40 concentrations were similar in familial Alzheimer's disease and sporadic Alzheimer's disease groups, while 3H-PiB binding was lower in the familial Alzheimer's disease than the sporadic Alzheimer's disease group. Higher amyloid-ß1-42 concentration associated with higher 3H-PiB binding in sporadic Alzheimer's disease but not familial Alzheimer's disease. 11C-PiB retention correlated with region-matched post-mortem amyloid-ß plaque load; however, familial Alzheimer's disease cases with abundant cotton wool plaques had lower 11C-PiB retention than sporadic Alzheimer's disease cases with similar amyloid-ß plaque loads. PiB has limited ability to detect amyloid-ß aggregates in cotton wool plaques and may underestimate total amyloid-ß plaque burden in brain regions with abundant cotton wool plaques.

Crossing N=28 Toward the Neutron Drip Line: First Measurement of Half-Lives at FRIB.

New half-lives for exotic isotopes approaching the neutron drip-line in the vicinity of N∼28 for Z=12-15 were measured at the Facility for Rare Isotope Beams (FRIB) with the FRIB decay station initiator. The first experimental results are compared to the latest quasiparticle random phase approximation and shell-model calculations. Overall, the measured half-lives are consistent with the available theoretical descriptions and suggest a well-developed region of deformation below ^{48}Ca in the N=28 isotones. The erosion of the Z=14 subshell closure in Si is experimentally confirmed at N=28, and a reduction in the ^{38}Mg half-life is observed as compared with its isotopic neighbors, which does not seem to be predicted well based on the decay energy and deformation trends. This highlights the need for both additional data in this very exotic region, and for more advanced theoretical efforts.

Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging.

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; ß = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

Low untreated systolic blood pressure over 18 years is associated with survival free of dementia age 90.

INTRODUCTION: We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95. METHODS: SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aß) and repeat clinical-cognitive evaluations every 6 months. RESULTS: By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aß was directly related to SBP levels. In multivariate analysis, Aß+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aß, SBP became a significant predictor of dementia. DISCUSSION: Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aß.

PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer's disease progression in Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aß) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aß throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aß to better characterize the natural history of Aß accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. METHODS: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aß burden was quantified using the amyloid load metric (AßL). Modeled PiB images were generated from the longitudinal AßL data to visualize which regions are most susceptible to Aß accumulation in DS. AßL change was evaluated across Aß(-), Aß-converter, and Aß(+) groups to assess longitudinal Aß trajectories during different stages of AD-pathology progression. AßL change values were used to identify Aß-accumulators within the Aß(-) group prior to reaching the Aß(+) threshold (previously reported as 20 AßL) which would have resulted in an Aß-converter classification. With knowledge of trajectories of Aß(-) accumulators, a new cutoff of Aß(+) was derived to better identify subthreshold Aß accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aß change with 80% power (alpha 0.01) were determined for different groups of Aß-status. RESULTS: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aß accumulation in DS. The Aß(-) group had a mean AßL change of 0.38 (0.58) AßL/year, while the Aß-converter and Aß(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AßL/year, respectively. Within the Aß(-) group, Aß-accumulators showed no significant difference in AßL change values when compared to Aß-converter and Aß(+) groups. An Aß(+) cutoff for subthreshold Aß accumulation was derived as 13.3 AßL. The estimated sample size necessary to detect a 25% reduction in Aß was 79 for Aß(-) accumulators and 59 for the Aß-converter/Aß(+) group in DS. CONCLUSION: Longitudinal AßL changes were capable of distinguishing Aß accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aß accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aß deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.

Safety and Outcomes of Prolonged Usual Care Prone Position Mechanical Ventilation to Treat Acute Coronavirus Disease 2019 Hypoxemic Respiratory Failure.

OBJECTIVES: Prone position ventilation is a potentially life-saving ancillary intervention but is not widely adopted for coronavirus disease 2019 or acute respiratory distress syndrome from other causes. Implementation of lung-protective ventilation including prone positioning for coronavirus disease 2019 acute respiratory distress syndrome is limited by isolation precautions and personal protective equipment scarcity. We sought to determine the safety and associated clinical outcomes for coronavirus disease 2019 acute respiratory distress syndrome treated with prolonged prone position ventilation without daily repositioning. DESIGN: Retrospective single-center study. SETTING: Community academic medical ICU. PATIENTS: Sequential mechanically ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. INTERVENTIONS: Lung-protective ventilation and prolonged protocolized prone position ventilation without daily supine repositioning. Supine repositioning was performed only when Fio2 less than 60% with positive end-expiratory pressure less than 10 cm H2O for greater than or equal to 4 hours. MEASUREMENTS AND MAIN RESULTS: Primary safety outcome: proportion with pressure wounds by Grades (0-4). Secondary outcomes: hospital survival, length of stay, rates of facial and limb edema, hospital-acquired infections, device displacement, and measures of lung mechanics and oxygenation. Eighty-seven coronavirus disease 2019 patients were mechanically ventilated. Sixty-one were treated with prone position ventilation, whereas 26 did not meet criteria. Forty-two survived (68.9%). Median (interquartile range) time from intubation to prone position ventilation was 0.28 d (0.11-0.80 d). Total prone position ventilation duration was 4.87 d (2.08-9.97 d). Prone position ventilation was applied for 30.3% (18.2-42.2%) of the first 28 days. Pao2:Fio2 diverged significantly by day 3 between survivors 147 (108-164) and nonsurvivors 107 (85-146), mean difference -9.632 (95% CI, -48.3 to 0.0; p = 0·05). Age, driving pressure, day 1, and day 3 Pao2:Fio2 were predictive of time to death. Thirty-eight (71.7%) developed ventral pressure wounds that were associated with prone position ventilation duration and day 3 Sequential Organ Failure Assessment. Limb weakness occurred in 58 (95.1%) with brachial plexus palsies in five (8.2%). Hospital-acquired infections other than central line-associated blood stream infections were infrequent. CONCLUSIONS: Prolonged prone position ventilation was feasible and relatively safe with implications for wider adoption in treating critically ill coronavirus disease 2019 patients and acute respiratory distress syndrome of other etiologies.

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-ß plaques in Alzheimer's disease.

Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-ß (Aß) deposits is high for detection of neuritic Aß plaques, a mature form of Aß deposits which often have dense Aß core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aß plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer's disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aß burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aß immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aß-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aß-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aß plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aß fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.

A stochastic epigenetic Mendelian oligogenic disease model for type 1 diabetes.

The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high-to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes.

Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology.

INTRODUCTION: We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB-positron emission tomography ([11C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aß-PET quantification. METHODS: Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. RESULTS: CL values increased with each CERAD neuritic plaque score increment (median -3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aß phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). DISCUSSION: Our study demonstrated the robustness of a multisite Centiloid [11C]PIB-PET study and established a range of pathology-based CL thresholds.

Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies.

OBJECTIVE: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. METHODS: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. RESULTS: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. INTERPRETATION: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128.

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

Structure-based discovery of LpxC inhibitors.

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.

Dopaminergic activity and altered reward modulation in anorexia nervosa-insight from multimodal imaging.

OBJECTIVE: Individuals with anorexia nervosa (AN) have anxious and inhibited temperaments with high concern for consequences. Studies using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) suggest involvement of the middle and dorsal caudate (DC) in individuals recovered (REC) from AN. For example, dopamine (DA) D2/D3 receptor binding in the middle caudate and DC was associated with anxiety and harm avoidance, and blood-oxygen-level-dependent (BOLD) response in the DC was positively related to trait anxiety. It has not been shown yet whether BOLD response in individuals REC from AN was related to DA function. METHODS: Post-hoc correlation analyses between the PET and fMRI studies by correlating D2/D3 binding in striatal regions and BOLD signal in the anteroventral striatum (AVS) and DC for wins and losses respectively in 12 individuals REC from AN. RESULTS: Individuals REC from AN with the greatest BOLD response in the DC in a monetary choice task had higher middle caudate D2/D3 binding, and greater anxiety and/or harm avoidance. DISCUSSION: Though preliminary, these findings suggest that increased dorsal striatal D2/D3 binding is associated with enhanced cognitive response to feedback, potentially related to anxious anticipation of consequences. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:593-596).