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Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.

Alzheimer’s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

We assessed whether carotid intima-media thickness (cIMT) is prospectively associated with amyloid-β (Aβ). 332 nondemented Atherosclerosis Risk in Communities Study participants with carotid ultrasounds (1990–1992) and PET scans (2012–2014) were studied. Participants in the highest (versus lowest) cIMT tertile had 2.17 times the odds of elevated Aβ (95% CI: 1.15–4.11), after demographic and APOE ɛ4 adjustments. An interaction with APOE ɛ4 was observed (p = 0.02). Greater cIMT was associated with elevated Aβ independent of vascular risk factors among those with ≥1 APOE ɛ4 allele, but not in noncarriers. In this cohort, higher cIMT was associated with Aβ deposition 22 years later, particularly among APOE ɛ4 carriers.

The aim of this study is to determine if there is an association between atrial arrhythmias and brain amyloid-β (Aβ), measured on florbetapir (FBP) PET. 346 nondemented participants from the Atherosclerosis Risk in Communities study underwent FBP-PET, 185 also wore Zio® XT Patch. The associations between global cortical Aβ (> 1.2 standardized uptake value ratio) and history of atrial fibrillation, zio-defined atrial tachycardia and premature atrial contractions, each, were evaluated. Among nondemented community-dwelling older adults, we did not find an association between atrial arrhythmias and Aβ. Other brain pathology may underlie the association described between atrial arrhythmias and cognition.

BACKGROUND Higher neuroticism and lower conscientiousness are risk factors for Alzheimer's disease and related dementias, but the underlying neuropathological correlates remain unclear. Our aim was to examine whether personality traits are associated with amyloid and tau neuropathology in a new sample and meta-analyses. METHODS Participants from the BLSA (Baltimore Longitudinal Study of Aging) completed the Revised NEO Personality Inventory and underwent amyloid (11C-labeled Pittsburgh compound B) and tau (18F-flortaucipir) positron emission tomography. RESULTS Among cognitively normal BLSA participants, neuroticism was associated with higher cortical amyloid burden (odds ratio 1.68, 95% confidence interval 1.20-2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% confidence interval 0.44-0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE e4. Similar associations were found with tau in the entorhinal cortex. Random-effects meta-analyses of 12 studies found that higher neuroticism (N = 3015, r = 0.07, p = .008) and lower conscientiousness (N = 2990, r = -0.11, p

Decryption of brain images is the basis for the necessary translation of the findings from imaging to information required to meet the demands of clinical intervention. Tools of brain imaging, therefore, must satisfy the conditions dictated by the needs for interpretation in terms of diagnosis and prognosis. In addition, the applications must serve as fundamental research tools that enable the understanding of new therapeutic drugs, including compounds as diverse as antipsychotics, antidepressants, anxiolytics, and drugs serving the relief of symptoms from neurochemical disorders as unrelated as multiple sclerosis, stroke, and dementia. Here we review and explain the kinetics of methods that enable researchers to describe the brain’s work and functions. We focus on methods invented by neurokineticists and expanded upon by practitioners during decades of experimental work and on the methods that are particularly useful to predict possible future approaches to the treatment of neurochemical disorders. We provide an overall description of the basic elements of kinetics and the underlying quantification methods, as well as the mathematics of modeling the recorded brain dynamics embedded in the images we obtain in vivo. The complex presentation to follow is necessary to justify the contribution of modeling to the development of methods and to support the specifications dictated by the proposed use in clinical settings. The quantification and kinetic modeling processes are equally essential to image reconstruction and labeling of brain regions of structural or functional interest. The procedures presented here are essential tools of scientific approaches to all conventional and novel forms of brain imaging. The foundations of the kinetic and quantitative methods are keys to the satisfaction of clinicians that actively engage in treating the neurochemical disorders of mammalian brains in the fields of neurology, neurosurgery, and neuropsychiatry.

Background: Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. Method: We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. Results: We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Conclusions: The estimates of BPND declined significantly with age in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade).

Values of binding potentials (BP

Background Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear. Methods We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years. Results At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital, and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas. Conclusion Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function.

We derived three widely used linearizations from the definition of receptor availability in molecular imaging with positron emission tomography (PET). The purpose of the present research was to determine the convergence of the results of the 3 methods in terms of 3 parameters—occupancy (s), distribution volume of the nondisplaceable reference binding compartment (V(ND)), and nondisplaceable reference binding potential (BP(ND)) of the radioligand—in the absence of a gold standard. We tested 104 cases culled from the literature and calculated the goodness of fit of the least-squares and Deming II methods of linear regression when applied to the determination of s, V(ND), and BP(ND) using the goodness-of-fit parameters R(2), coefficient of variation (root-mean-square error [RMSE]), and the infinity norm (‖X‖(∞)) with both regression methods. We observed superior convergence among the values of s, V(ND), and BP(ND) for the inhibition and occupancy plots. The inhibition plot emerged as the plot with a slightly higher degree of convergence (based on R(2), RMSE, and ‖X‖(∞) value). With two regression methods (the least-squares method [LSM] and the Deming II [DM] method), the estimated values of s, V(ND), and BP(ND) generally converged. The inhibition and occupancy plots yielded the best fits to the data, according to the goodness-of-fit parameters, due primarily to absence of commingling of the dependent and independent variables tested with the saturation (original Lassen) plot. In the presence of noise, the inhibition and occupancy plots yielded higher convergences.

Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood.Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models.In 298 individuals, 36 developed dementia (median follow-up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72-3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18-5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03-2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18-4.01).Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Imaging markers of cerebrovascular disease and Alzheimer’s disease (AD) are implicated in mobility impairment in older adults, but few studies have examined these relationships longitudinally in a racially-diverse population-based sample. At Visit 5 (2011–13) of the ARIC Study, 1859 participants had usual pace gait speed (cm/s) assessed and brain MRI (mean age = 76.3, 28.5% Black) and PET (n = 343; mean age = 75.9, 42.6% Black) measures including total/regional brain volume (cm(3)), white matter hyperintensities (WMH; cm(3)), infarcts (present/absent), microbleeds (count) and global beta-amyloid (Aβ). Participants returned at Visit 6 (n = 1264, 2016–17) and Visit 7 (n = 1108, 2018–19) for follow-up gait speed assessments. We used linear regression to estimate effects of baseline infarct presence, higher microbleed count, and a one interquartile range (IQR) poorer measures of continuous predictors (−1 IQR total brain volume, temporal-parietal lobe meta region of interest(ROI); +1 IQR WMH volume, global Aβ SUVR) on cross-sectional gait speed and change in gait speed adjusting for age, sex, education, study site, APOE e4, estimated intracranial volume, BMI, and cardiovascular risk factors. Cross-sectionally, slower gait speed outcome was associated with higher WMH volume, −3.38 cm/s (95%CI:−4.71, −2.04), infarct presence, −5.60 cm/s (−7.69, −3.51), microbleed count, −2.20 cm/s (−3.20, −0.91), smaller total brain volume, −9.26 cm/s (−12.1, −6.43), and smaller temporal-parietal lobe ROI −6.28 cm/s (−8.28, −4.28). Longitudinally, faster gait speed outcome decline was associated with higher WMH volume, −0.27 cm/s/year, (−0.51, −0.03) and higher global Aβ SUVR, −0.62 cm/s/year (−1.20, −0.03). Both cerebrovascular and AD pathology may contribute to mobility decline commonly seen with aging.

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities–Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.

Purpose The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin–dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25–6 mg. Methods Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. Results Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77–88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74–83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration–time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. Conclusion By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. Trial registration ClinicalTrials.gov NCT00805454 December 9, 2008.

BackgroundAs more older adults undergo surgery, it is critical to understand the long-term effects of surgery on brain health, particularly in relation to the development of Alzheimer’s disease. This study examined the association of surgical hospitalization with subsequent brain β-amyloid deposition in nondemented older adults.MethodsThe Atherosclerosis Risk in Communities–Positron Emission Tomography (ARIC–PET) study is a prospective cohort study of 346 participants without dementia who underwent florbetapir PET imaging. Active surveillance of local hospitals and annual participant contact were used to gather hospitalization and surgical information (International Classification of Disease, Ninth Revision, Clinical Modification codes) over the preceding 24-yr period. Brain amyloid measured using florbetapir PET imaging was the primary outcome. Elevated amyloid was defined as a standardized uptake value ratio of more than 1.2.ResultsOf the 313 participants included in this analysis (age at PET: 76.0 [SD 5.4]; 56% female), 72% had a prior hospitalization, and 50% had a prior surgical hospitalization. Elevated amyloid occurred in 87 of 156 (56%) participants with previous surgical hospitalization, compared with 45 of 87 (52%) participants who had no previous hospitalization. Participants with previous surgical hospitalizations did not show an increased odds of elevated brain amyloid (odds ratio, 1.32; 95% CI, 0.72 to 2.40; P = 0.370) after adjusting for confounders (primary analysis). Results were similar using the reference group of all participants without previous surgery (hospitalized and nonhospitalized; odds ratio, 1.58; 95% CI, 0.96 to 2.58; P = 0.070). In a prespecified secondary analysis, participants with previous surgical hospitalization did demonstrate increased odds of elevated amyloid when compared with participants hospitalized without surgery (odds ratio, 2.10; 95% CI, 1.09 to 4.05; P = 0.026). However, these results were attenuated and nonsignificant when alternative thresholds for amyloid-positive status were used.ConclusionsThe results do not support an association between surgical hospitalization and elevated brain amyloid.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Sleep disturbance predicts worse pain outcomes. Because sleep disturbance inequitably impacts Black adults - with racism as the upstream cause - understanding how racism-related stress impacts pain through sleep might help minimize racialized pain inequities. This preliminary study examined sequential mediation of the effect of racism-related stress on experimental pain through sleep disturbance and corticolimbic μOR function in pain-free non-Hispanic Black (NHB) and White (NHW) adults. Participants completed questionnaires, actigraphy, positron emission tomography, and sensory testing. We reproduced findings showing greater sleep disturbance and pain sensitivity among NHB participants; greater sleep disturbance (r = .35) and lower pain tolerance (r=-.37) were significantly associated with greater racism-related stress. In a sequential mediation model, the total effect of racism-related stress on pain tolerance (β=-.38, P = .005) weakened after adding sleep disturbance and ventromedial prefrontal cortex (vmPFC) μOR binding potential (BP

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of b-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging.