Search

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Individuals with familial Alzheimer’s disease due to PSEN1 mutations develop high cortical fibrillar amyloid-β 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-β 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-β-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-β1-40 and amyloid-β1-42. 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-β42 antibodies but weakly with amyloid-β40 and amyloid-βN3pE antibodies and had only background cyano-PiB fluorescence despite labelling with X-34. Relative to amyloid-β 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-β1-42 and amyloid-β1-40 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-β1-42 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-β 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-β plaque loads. PiB has limited ability to detect amyloid-β aggregates in cotton wool plaques and may underestimate total amyloid-β plaque burden in brain regions with abundant cotton wool plaques.

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct ‘neuroinflammatory signatures’. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. ‘radicular’ versus ‘axial’ back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of ‘fibromyalgianess’ (i.e. the degree of pain centralization, or ‘nociplastic pain’). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex–thalamus connectivity across groups. Our findings support the existence of ‘neuroinflammatory signatures’ that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

[

Positron emission tomography and magnetic resonance imaging (PET/MRI) scanners cannot be qualified in the manner adopted for hybrid PET and computed tomography (CT) devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms due to the difficulty in converting the MRI images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MR-based algorithms have been developed to more accurately derive the attenuation properties of the human head, including the skull. Although very promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head attenuation correction from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MR- and CT-based AC methods and whole-brain qualitative and quantitative (both voxel-wise and regional) analyses should be performed. The MR-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified herein. We have implemented this approach successfully across two PET/MRI scanner manufacturers at two sites.

The positron emission tomography (PET) radiotracer [11C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [11C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [11C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [11C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [11C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [11C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.

The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [[In region of interest analyses, ECs exhibited significantly lower [This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.

The risk for coronary artery disease (CAD) is substantially increased in type 1 diabetes and it has been postulated that insulin resistance may contribute to this risk. The current study measured insulin resistance in type 1 diabetes with vs without CAD and with a focus upon skeletal muscle, to test the hypothesis that insulin resistance is more severe in participants who have type 1 diabetes and CAD. Additionally, in type 1 diabetes, we examined the hypothesis that insulin resistance is more severe in soleus (an oxidative type muscle) vs tibialis anterior (a more glycolytic type of muscle). Insulin resistance was measured in participants with type 1 diabetes with (n = 9, CAD+) and without CAD (n = 10, CAD−) using euglycaemic insulin infusions combined with positron emission tomography (PET) imaging of [18F]fluorodeoxyglucose (FDG) uptake into soleus and tibialis anterior skeletal muscles. Coronary artery calcium (CAC) score was quantified by electron beam tomography. CAD+ participants with type 1 diabetes had a >100-fold higher CAC score than did CAD− participants with type 1 diabetes but groups did not differ in HbA1c or insulin dose. During clamp studies, CAD+ and CAD− groups had similar glucose disposal but were insulin resistant compared with historical non-diabetic participants (n = 13). FDG uptake by soleus muscle was similarly reduced, overall, in individuals with type 1 diabetes with or without CAD compared with non-diabetic individuals. However, FDG uptake by tibialis anterior muscle was not reduced in CAD− participants with type 1 diabetes while in CAD+ participants with type 1 diabetes it was 75% greater (p

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the computation of reward prediction errors. However, competing evidence supports human dopamine signaling in the basal ganglia as also contributing to the generation of higher order learning heuristics. Here, we present data from a large (N=81, 18-30yo), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [

ObjectiveTo determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.MethodsThirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.ResultsCompared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.ConclusionsThese findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Background Restricting time in bed improves insomnia symptoms, but the neural mechanisms for this effect are unknown. Total and partial acute sleep restriction may be useful paradigms for elucidating these effects. We examined the impact of acute sleep restriction on cerebral glucose metabolism during non-rapid eye movement (NREM) sleep in individuals with primary insomnia (n = 17) and good sleep (n = 19). Methods Participants underwent [18F]fluorodeoxyglucose positron emission tomography scans during baseline and recovery NREM sleep following one night of partial or total sleep restriction. We compared group differences in baseline-recovery changes, as well as main effects of group and condition (baseline vs. recovery NREM sleep), for relative regional cerebral metabolic rate for glucose (rCMRglc), whole-brain glucose metabolism, and sleep quality. Results Relative rCMRglc was significantly lower during recovery NREM sleep compared to baseline in the left frontoparietal cortex, medial frontal cortex, posterior cingulate cortex, and thalamus, with no significant group differences. Good sleepers, but not insomnia patients, had lower whole-brain glucose metabolism during recovery NREM sleep compared to baseline. Acute sleep restriction improved sleep quality in individual with insomnia. Subgroup analyses including only participants who underwent partial sleep restriction yielded the same pattern of findings. Conclusion Individuals with insomnia and good sleepers showed similar relative rCMRglc responses to acute sleep restriction. Brain regions showing the greatest baseline-recovery changes in both groups included regions previously shown to have smaller sleep-wake differences in patients with primary insomnia. Acute sleep restriction, and by extension sleep restriction therapy, may impact regional metabolic alterations that characterize insomnia.

11C-Raclopride (RAC) positron emission tomography (PET) is used to study dopamine response to pharmacological and behavioral challenges. Behavioral challenges produce smaller responses than pharmacological challenges and are more susceptible to sources of bias, including motion bias. The purpose of this study was to characterize the effect of motion bias within the context of a behavioral task challenge, examining the impact of different motion correction strategies, different task response magnitudes, and intra-versus interframe motion.MethodsSeventy healthy young adults were administered bolus plus constant infusion 11C-Raclopride (RAC) and imaged for 90 min on a 3-Tesla simultaneous PET/magnetic resonance (MR) scanner during which a functional MRI (fMRI) reward task experiment was conducted. Kinetic analysis was performed using an extension of the multilinear reference tissue model (MRTM), which encoded the task response as a unit step function at the start of the task (t = 40 min). The quantitative impacts of different approaches to motion correction (frame-based, reconstruction-based, none) were compared using voxel maps of change in binding potential (ΔBPND). Motion bias was compared to task effect by simulating different levels of ΔBPND (0%, 5%, 10%, 20%) in conjunction with simulating high and no motion. Intraframe motion was simulated using motion estimates derived from the simultaneously acquired MR data. The relative impact of intraframe motion was evaluated by comparing maps of bias in ΔBPND before and after applying frame-based motion correction.ResultsAmong the high-motion subjects, failure to perform motion correction resulted in large artifacts. Frame- and reconstruction-based approaches both corrected for motion effectively, with the former showing moderately more intense ΔBPND values (both positive and negative) in and around the striatum. At low task response magnitudes, simulations showed that motion bias can have a greater relative effect. At 5% ΔBPND, motion bias accounted for 60% of the total bias, while at 10% ΔBPND, it accounted for only 34%. Simulating high-temporal resolution motion, frame-based motion correction was shown to counteract the majority of the of the motion bias effect. The remaining bias attributable to intraframe motion accounted for only 8% of the total.ConclusionMotion bias can have a corrupting effect on RAC studies of behavioral task challenges, particularly as the magnitude of the response decreases. Applying motion correction mitigates most of the bias, and specifically correcting for interframe motion provides the bulk of the benefit.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-beta (A beta) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before A beta in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, A beta burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked A beta-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global A beta burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Research suggests a link between Alzheimer’s Disease in Down Syndrome (DS) and the overexpression of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant’s structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable, mild cognitive impairment (MCI-DS), and dementia) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to our ground truth individual MRI-based segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the ground truth by using DS group atlases that aligns with a participant’s disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the ground truth than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using a disease-state specific atlas. All atlases are made publicly available for the research community.AbbreviationsAD, DS, Aβ, DSG, CS-DS, CS-NT, LOOCV, ROI, MSE, MRI, PET, JLF, CS, MCI-DS, DEM.

Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing in computing prediction errors, which form the basis of reward learning behaviors. However, direct evidence demonstrating how human dopamine signaling in the basal ganglia contributes to learning has been hampered by limitations of individual imaging modalities. Here, we present data from a large (N=81, 18-30 year olds), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [11C]Raclopride (RAC) assessing striatal D2/3 receptor binding. Results indicated that task-related dopamine release in the ventral striatum, measured as a change in RAC binding, was greater among those who demonstrated successful reward learning on a probabilistic map learning task. This learning response was specific to the ventral striatum and was not present in fMRI BOLD reward response activation. This provides support for considering task-related DA release in ventral striatum as a key signal for translating reward outcomes into a learning signal, rather the representing the reward outcome in isolation. These data provide novel, human in vivo evidence that dopaminergic function may support reward reactivity as well as reward learning as distinct processes.

Down syndrome (DS) predisposes individuals to early Alzheimer's disease (AD). Using Pittsburgh Compound B ([11C]PiB), a pattern of striatal amyloid beta (Aβ) that is elevated relative to neocortical binding has been reported, similar to that of nondemented autosomal dominant AD mutation carriers. However, it is not known whether changes in striatal and neocortical [11C]PiB retention differ over time in a nondemented DS population when compared to changes in a nondemented elderly (NDE) population. The purpose of this work was to assess longitudinal changes in trajectories of Aβ in a nondemented DS compared to an NDE cohort. The regional trajectories for anterior ventral striatum (AVS), frontal cortex, and precuneus [11C]PiB retention were explored over time using linear mixed effects models with fixed effects of time, cohort, and time-by-cohort interactions and subject as random effects. Significant differences between DS and NDE cohort trajectories for all 3 region of interests were observed (p < 0.05), with the DS cohort showing a faster accumulation in the AVS and slower accumulation in the frontal cortex and precuneus compared to the NDE cohort. These data add to the previously reported distinct pattern of early striatal deposition not commonly seen in sporadic AD by demonstrating that individuals with DS may also accumulate Aβ at a rate faster in the AVS when compared to NDE subjects.

The focus of Alzheimer’s disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome (DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population. Further, the use of typical MRI to MRI template spatial normalization is less desirable in this cohort due to a greater presence of motion artefacts in MRI images. The diffuse nature of PiB uptake and comparatively lower spatial resolution of the PET image permits the purposing of this modality as a template for spatial normalization, which can substantially improve the robustness of this procedure in the cases of MRI images with motion. The aim of this work was to establish standardized methods for spatial normalization and tissue type segmentation using DS specific templates in order to perform voxel-wise analyses. A total of 72 adults with DS underwent [11C]PiB PET to assess brain amyloid burden and volumetric MRI imaging. A DS specific PiB template for spatial normalization and a set of DS specific prior probability templates were created with two-pass methods. With implementation of this DS specific PiB template, no participants were excluded due to poor spatial normalization, thus maximizing the sample size for PiB analyses in standardized space. In addition, difference images between prior probability templates created from the general population and the DS population reflected known morphological differences, particularly in the frontal cortex. In conclusion, DS specific templates that account for unique challenges improve spatial normalization and tissue type segmentation, and provide a framework for reliable voxel-wise analysis of AD biomarkers in this atypical population.

Background Subject motion in positron emission tomography (PET) studies leads to image blurring and artifacts; simultaneously acquired magnetic resonance imaging (MRI) data provides a means for motion correction (MC) in integrated PET/MRI scanners. Purpose To assess the effect of realistic head motion and MR-based MC on static [18 F]-fluorodeoxyglucose (FDG) PET images in dementia patients. Study type Observational study. Population Thirty dementia subjects were recruited. Field strength/sequence 3T hybrid PET/MR scanner where EPI-based and T1 -weighted sequences were acquired simultaneously with the PET data. Assessment Head motion parameters estimated from high temporal resolution MR volumes were used for PET MC. The MR-based MC method was compared to PET frame-based MC methods in which motion parameters were estimated by coregistering 5-minute frames before and after accounting for the attenuation-emission mismatch. The relative changes in standardized uptake value ratios (SUVRs) between the PET volumes processed with the various MC methods, without MC, and the PET volumes with simulated motion were compared in relevant brain regions. Statistical tests The absolute value of the regional SUVR relative change was assessed with pairwise paired t-tests testing at the P = 0.05 level, comparing the values obtained through different MR-based MC processing methods as well as across different motion groups. The intraregion voxelwise variability of regional SUVRs obtained through different MR-based MC processing methods was also assessed with pairwise paired t-tests testing at the P = 0.05 level. Results MC had a greater impact on PET data quantification in subjects with larger amplitude motion (higher than 18% in the medial orbitofrontal cortex) and greater changes were generally observed for the MR-based MC method compared to the frame-based methods. Furthermore, a mean relative change of ∼4% was observed after MC even at the group level, suggesting the importance of routinely applying this correction. The intraregion voxelwise variability of regional SUVRs was also decreased using MR-based MC. All comparisons were significant at the P = 0.05 level. Data conclusion Incorporating temporally correlated MR data to account for intraframe motion has a positive impact on the FDG PET image quality and data quantification in dementia patients. Level of evidence 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1288-1296.

PURPOSE: In dual modality Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), attenuation correction (AC) methods are continually improving. Although a new AC can sometimes be generated from existing MR data, its application requires a new reconstruction. We evaluate an approximate 2D projection method that allows offline image-based reprocessing. PROCEDURE: 2-Deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) brain scans were acquired (Siemens HR+) for 6 subjects. Attenuation data were obtained using the scanner’s transmission source (SAC). Additional scanning was performed on a Siemens mMR including production of a Dixon-based MR AC (MRAC). The MRAC was imported to the HR+ and the PET data were reconstructed twice: once using native SAC (ground truth); once using the imported MRAC (imperfect AC). The re-projection method was implemented as follows. The MRAC PET was forward projected to approximately reproduce attenuation-corrected sinograms. The SAC and MRAC images were forward projected and converted to attenuation-correction factors (ACFs). The MRAC ACFs were removed from the MRAC PET sinograms by division; the SAC ACFs were applied by multiplication. The regenerated sinograms were reconstructed by filtered back projection to produce images (SUBAC PET) in which SAC has been substituted for MRAC. Ideally SUBAC PET should match SAC PET. Via coregistered T1 images, FreeSurfer (FS; MGH, Boston) was used to define a set of cortical gray matter regions of interest (ROIs). Regional activity concentrations were extracted for SAC PET, MRAC PET, and SUBAC PET. RESULTS: SUBAC PET showed substantially smaller root mean square error than MRAC PET with averaged values of 1.5% versus 8.1%. CONCLUSIONS: Re-projection is viable image-based method for application of an alternate attenuation correction in neuroimaging.

Background The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD). Objective The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Author(s): Keator, David B; Phelan, Michael J; Taylor, Lisa; Doran, Eric; Krinsky-McHale, Sharon; Price, Julie; Ballard, Erin E; Kreisl, William C; Hom, Christy; Nguyen, Dana; Pulsifer, Margaret; Lai, Florence; Rosas, Diana H; Brickman, Adam M; Schupf, Nicole; Yassa, Michael A; Silverman, Wayne; Lott, Ira T | Abstract: IntroductionDown syndrome (DS) is associated with a higher risk of dementia. We hypothesize that amyloid beta (Aβ) in specific brain regions differentiates mild cognitive impairment in DS (MCI-DS) and test these hypotheses using cross-sectional and longitudinal data.Methods18F-AV-45 (florbetapir) positron emission tomography (PET) data were collected to analyze amyloid burden in 58 participants clinically classified as cognitively stable (CS) or MCI-DS and 12 longitudinal CS participants.ResultsThe study confirmed our hypotheses of increased amyloid in inferior parietal, lateral occipital, and superior frontal regions as the main effects differentiating MCI-DS from the CS groups. The largest annualized amyloid increases in longitudinal CS data were in the rostral middle frontal, superior frontal, superior/middle temporal, and posterior cingulate cortices.DiscussionThis study helps us to understand amyloid in the MCI-DS transitional state between cognitively stable aging and frank dementia in DS. The spatial distribution of Aβ may be a reliable indicator of MCI-DS in DS.

The goal of this chapter is to provide the reader with a basic understanding of Positron Emission Tomography (PET) imaging and simultaneous PET and magnetic resonance (or PET/MR) imaging. These topics are presented with particular emphasis on PET as a molecular imaging tool and MRI as a structural and functional imaging tool. The chapter begins with an introduction to the underlying PET physics and a brief review of how data are acquired and reconstructed into 3D images. This includes common corrections that are applied to minimize image artifacts and improve accuracy, as well as a brief discussion of key advantages and limitations of PET and MRI and the benefits of combined PET/MR imaging. The strengths of PET as a molecular imaging technology are then presented in the context of in vivo imaging of protein targets that are relevant to schizophrenia and other neuropsychiatric disorders. This includes a basic review of PET pharmacokinetic methods used to evaluate radioligand-protein binding interactions and simpler and more feasible methods used for routine PET assessments. The final section presents a discussion of future directions and recent advances in PET/MR imaging applications.

Objective Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT. Interpretation A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.

IR in T1D may contribute to CAD risk. We recently reported that SM IR in T1D primarily involves oxidative SM while glycolytic SM is comparable to healthy controls. This study compared systemic glucose disposal (GD) and SM IR in T1D with and without CAD. Insulin-infusion glucose clamps measured systemic GD concurrent with positron emission tomography (PET) imaging of SM glucose uptake with [18F]fluorodeoxyglucose (FDG) to profile glucose transport and phosphorylation, rate-limiting steps for GD. PET images were co-registered with MRI of the calf to determine FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative muscle, type 1 fibers) vs. tibialis anterior (TA) SM (largely glycolytic muscle, type 2 fibers). Subjects with (n=9) and without (n=10) CAD were from the Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Those CAD+ were older (52.4 vs. 43.1 years, p Disclosure K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc. Funding National Institutes of Health (DK071487)

In addition to a severe deficiency of insulin secretory capacity, systemic IR has also been identified as contributing to the pathophysiology of T1D. This study was undertaken to examine the contribution of SM, the major site for insulin-stimulated glucose uptake, to the IR of T1D, and more specifically, the role of impaired glucose transport. During euglycemic insulin infusion, dynamic PET imaging of SM was done using [18F]fluorodeoxyglucose (FDG), the metabolism of which is restricted to transport/phosphorylation. PET images were co-registered with calf MRI to assess and compare FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative, type 1 fiber) and in tibialis anterior (TA) SM (largely glycolytic, type 2 fiber) to determine the respective severity of IR in these two types of SM. Systemic IR was assessed as glucose disposal rate (GDR) during the clamps. Participants (n=10) with T1D with no evidence of coronary artery or renal disease were recruited from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Mean HbA1c in T1D was 7.6±1.3%. Nondiabetic healthy controls (n=13) of comparable age (40.4 years) and BMI (24.1 kg/m2) as the T1D group (43.1 years, 24.3 kg/m2) were studied. Systemic IR was evident in T1D, with GDR reduced by ∼25% (4.95 vs. 6.60 mg/kg-FFM, p=0.06). SM IR was clearly present in oxidative SO SM in T1DM, as values for K were reduced by nearly 50% (0.0075 vs. 0.0126 mL/cm3-minutes, p Disclosure K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc. Funding National Institutes of Health (DK071487)

Author(s): Bailer, Ursula F; Price, Julie C; Meltzer, Carolyn C; Wagner, Angela; Mathis, Chester A; Gamst, Anthony; Kaye, Walter H | Abstract: ObjectiveIndividuals 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.MethodsPost-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.ResultsIndividuals 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.DiscussionThough 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).

IMPORTANCE Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) epsilon 4 status and beta-amyloid (A beta). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.OBJECTIVE To examine sex differences in the cross-sectional association between A beta and regional tau deposition as measured with positron emission tomography (PET).DESIGN, SETTING AND PARTICIPANTS This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and A beta PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F-18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET.MAIN OUTCOMES AND MEASURES A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global A beta as well as sex and APOE epsilon 4 on these regions after controlling for age were also examined.RESULTS The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE epsilon 4 carriers [31%]; 89 individuals [30%] with high A beta. There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: beta [male] = -0.11 [0.05]; 95% CI,-0.21 to -0.02; P=.02), which was associated with individuals with higher AB burden. A sex by APOE epsilon 4 interaction was not associated with regional tau (meta-analytic estimate: beta [male, APOE epsilon 4+] = -0.15 [0.09]; 95% Cl, -0.32 to 0.01; P=.07).CONCLUSIONS AND RELEVANCE Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Introduction In cognitively healthy older adults, amyloid-beta (Aβ) burden is associated with greater activity on task-based functional magnetic resonance imaging. Higher levels of functional activation are associated with other factors along with amyloid and the authors investigated these relationships as well as how they relate to Aβ in cognitively healthy older adults. Methods The authors recruited cognitive healthy older adults (N = 50) from the Pittsburgh community that underwent extensive cognitive batteries, activation during a working memory (digit symbol substitution task, DSST), positron emission tomography scan for Pittsburgh Compound B (PiB, measuring amyloid), and other demographic measures. The authors tested the association between DSST activation and global PiB, neurocognitive batteries, and education. Results The authors found that the DSST robustly activated expected structures involved in working memory. The authors found that greater global Aβ deposition was associated with greater DSST activation in the right calcarine, precuneus, middle temporal as well as the left insula and inferior frontal gyrus. The authors also found that greater education was associated with lower DSST activation – however this was not significant after adjusting for Aβ. Discussion Greater amyloid was associated with greater activation, which may represent compensatory activation. Greater education was associated with lower activation, which may represent more efficient activation (i.e., less activation for the same task). After adjusting for amyloid, education was not significantly associated with activation suggesting that during the preclinical stage amyloid is the primary determinant of activation. Further, activation was not associated with cognitive function. Compensatory activation in the preclinical stage may help maintain cognitive function.

The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-[Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B (11C-PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline. Until recently it was not possible to visualize tau deposition in-vivo, but several tau PET tracers are now available in different stages of clinical development. To date, no tau tracer has been approved by the Food and Drug Administration for use in the evaluation of AD or other tauopathies, despite very active research efforts. In this paper we review the recent developments in tau PET imaging with a focus on in-vivo findings in AD and discuss the challenges associated with tau tracer development, the status of development and validation of different tau tracers, and the clinical information these provide.

Subjective complaints about memory and thinking abilities are commonly reported in older adults, with large variation in prevalence estimates (ranging from 25–55% in community-based studies) [1, 2]. Evidence from longitudinal studies indicates complaints confer a degree of elevated risk for subsequent cognitive decline and/or incident dementia/Alzheimer Disease (AD) [3, 4], although there is considerable variability among studies. Reviews also emphasized that determinants of subjective memory complaints (SMCs) in aging are complex and include individual differences in mood and personality [3, 5]. Over the past decade, evidence has accumulated of AD-biomarker associations with subjective memory concerns in otherwise cognitively normal older individuals. Glucose hypometabolism [6, 7], hippocampal atrophy[8, 9], APOE*4 allele status [10, 11], CSF amyloid-beta (Aβ) and tau [12], and amyloid-beta (Aβ) imaging [13, 14] may be linked to subjective memory complaints. Other reports included associations with other neuroimaging biomarkers, such as white matter hyperintensities [15, 16]. Several functional MRI studies demonstrated altered task-related activation [17, 18] or increased [19] / decreased [20] default mode network (DMN) connectivity associated with subjective memory complaints. This line of research is relevant to the NIA-AA proposed staging categories for preclinical AD [21], particularly stage III defined by amyloidosis and early neurodegenerative markers accompanied by subtle cognitive/behavioral decline. This last stage of preclinical AD in the model putatively captures individuals approaching the border zone with clinical criteria for mild cognitive impairment (MCI). As noted in the NIA-AA recommendations on defining preclinical stages of AD [21], subjective memory complaints in otherwise healthy individuals are consistent with the construct of ‘subtle cognitive decline’ [22]. This pilot study reports initial findings on Aβ imaging in patients who have presented to a memory-disorders clinic with cognitive concerns but with normal objective evaluation. Previous studies of subjective memory complaints and Aβ imaging have been inconsistent, with several studies reporting associations [13, 14, 23] and others finding no association [24, 25]. These studies included volunteers completing symptom inventories and self-report measures in a research setting, but otherwise not complaining in a clinically significant context (‘questionnaire-discovered complaints’). The present paper focuses on individuals having sufficient concern about their memory to motivate spontaneous complaint in a clinical setting (‘presenting complainers’). This narrow selection criterion limits generalizability of study findings but is of more direct relevance to the common scenario of the “worried well” in a practice setting [26]. The longer-term study goal is to determine the clinical and prognostic significance of Aβ in subjective cognitive decline (SCD) presenting in this context. In addition to Aβ imaging with Pittsburgh compound B (PiB)-PET, we evaluated subjective cognitive symptoms, depressive symptoms, personality, and performance on more challenging / specific cognitive tasks. In this preliminary report, we hypothesized that clinically presenting SCD individuals will have higher greater Aβ load compared to cognitively normal (CN) older study volunteers.

Objective Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; and to explore personality factors as potential moderators of this association. Design Cross-sectional observational study. Setting Clinical neuroimaging research center. Participants Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. Measurements Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. Results One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta = −0.230, p = 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint–high amyloid-β association. Conclusion Evidence for association between subjective cognition and brain amyloid-β deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ–amyloid-β association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease.

© 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. Introduction This article reviews the work done in the Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) core over the past 5 years, largely concerning techniques, methods, and results related to amyloid imaging in ADNI. Methods The PET Core has used [18F]florbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of [18F]fluorodeoxyglucose (FDG)-PET in clinical trials, and relationships between different biomarkers and cognition. Results Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale. Conclusion The PET Core has demonstrated a variety of methods for the standardization of biomarkers such as florbetapir PET in a multicenter setting.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology.PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-β deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region.Multiple linear regression revealed slight but highly significant (corrected P.05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex.There is an age-related amyloid-β deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.

Epigenetic mechanisms mediated by histone deacetylases (HDACs) have been implicated in a wide-range of CNS disorders and may offer new therapeutic opportunities. In vivo evaluation of HDAC density and drug occupancy has become possible with [(11)C]Martinostat, which exhibits selectivity for a subset of class I/IIb HDAC enzymes. In this study, we characterize the kinetic properties of [(11)C]Martinostat in the nonhuman primate (NHP) brain in preparation for human neuroimaging studies. The goal of this work was to determine whether classic compartmental analysis techniques were appropriate and to further determine if arterial plasma is required for future NHP studies. Using an arterial plasma input function, several analysis approaches were evaluated for robust outcome measurements. [(11)C]Martinostat showed high baseline distribution volume (VT) ranging from 29.9 to 54.4 mL/cm(3) in the brain and large changes in occupancy (up to 99%) with a blocking dose approaching full enzyme saturation. An averaged nondisplaceable tissue uptake (VND) of 8.6 ± 3.7 mL/cm(3) suggests high specific binding of [(11)C]Martinostat. From a two-tissue compartment model, [(11)C]Martinostat exhibits a high K1 (averaged K1 of 0.65 mL/cm(3)/min) and a small k4 (average of 0.0085 min(-1)). Our study supports that [(11)C]Martinostat can be used to detect changes in HDAC density and occupancy in vivo and that simplified analysis not using arterial blood could be appropriate.

Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer's disease, although Aβ alone may be insufficient to cause impairments. Modifiable health factors, including sleep, may mitigate functional symptoms of neurodegeneration. We assessed whether sleep moderated the relationship between Aβ and cognitive performance in 41 older adults, mean age 83 years. Sleep measures included actigraphy-assessed wake after sleep onset and total sleep time. Cognitive performance was assessed with memory recall, cognitive flexibility, and verbal fluency. Memory recall was assessed with the Rey-Osterrieth Complex Figure task, cognitive flexibility with the Trail Making test, and verbal fluency with FAS word generation. Aβ was assessed with a global measure of Pittsburgh Compound B. Wake after sleep onset moderated the relationship between Aβ and memory, with a stronger positive association for Aβ and forgetting in those with poorer sleep. These results suggest a possible protective role of sleep in preclinical Alzheimer's disease.