Background Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples. Methods We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer’s Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295). Results The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB − 151.87; threshold=1.08, 18 CL [18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP − 189.16; threshold=1.11, 20 CL [18F]FBB: CLcomposite = 244.20 × SUVRFBB − 170.80 [18F]FBP: CLcomposite = 300.66 × SUVRFBP − 208.84 Conclusions FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.

To characterize the influence of APOE genotype on cerebral Aβ load and longitudinal Aβ trajectories, [ 11 C]PiB PET imaging studies were performed in a cohort of 428 participants with known APOE genotype and a range of clinical diagnoses from cognitively normal elderly to Alzheimer's disease (AD). [ 11 C]PiB PET imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants. Serial [ 11 C]PiB data and a repeated measures

IntroductionThe population of older adults with Alzheimer’s disease and Related Dementias (ADRD) is growing larger and more diverse. Prevalence of ADRD is higher in African American (AA) and Hispanic populations relative to non-Hispanic whites (nHW), with larger differences for women compared to men of the same race. Given the public health importance of this issue, we sought to determine if AA and Hispanic women exhibit worse ADRD pathology compared to men of the same race and nHW women. We hypothesized that such differences may explain the discrepancy in ADRD prevalence.MethodsWe evaluated 932 articles that measured at least one of the following biomarkers of ADRD pathology in vivo and/or post-mortem: beta-amyloid (Aß), tau, neurodegeneration, and cerebral small vessel disease (cSVD). Criteria for inclusion were: (1) mean age of participants >65 years; (2) inclusion of nHW participants and either AA or Hispanics or both; (3) direct comparison of ADRD pathology between racial groups.ResultsWe included 26 articles (Aß = 9, tau = 6, neurodegeneration = 16, cSVD = 18), with seven including sex-by-race comparisons. Studies differed by sampling source (e.g., clinic or population), multivariable analytical approach (e.g., adjusted for risk factors for AD), and cognitive status of participants. Aß burden did not differ by race or sex. Tau differed by race (AA < nHW), and by sex (women > men). Both severity of neurodegeneration and cSVD differed by race (AA > nHW; Hispanics < nHW) and sex (women < men). Among the studies that tested sex-by-race interactions, results were not significant.ConclusionFew studies have examined the burden of ADRD pathology by both race and sex. The higher prevalence of ADRD in women compared to men of the same race may be due to both higher tau load and more vulnerability to cognitive decline in the presence of similar Aß and cSVD burden. AA women may also exhibit more neurodegeneration and cSVD relative to nHW populations. Studies suggest that between-group differences in ADRD pathology are complex, but they are too sparse to completely explain why minority women have the highest ADRD prevalence. Future work should recruit diverse cohorts, compare ADRD biomarkers by both race and sex, and collect relevant risk factor and cognitive data.

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 [15O]H2O and [18F]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 P2X7 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.

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.