Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and ß-amyloid (Aß) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aß or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aß PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aß in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aß (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aß differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets.

Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

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

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

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

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

Neural correlates of slower gait in middle-aged persons with childhood-onset type 1 diabetes mellitus: The impact of accelerated brain aging.

AIMS: We aimed to determine if neuroimaging characteristics of gray and white matter are associated with gait speed in middle-aged individuals with childhood-onset type 1 diabetes (T1D), and whether associations are independent of diabetic peripheral neuropathy (DPN) status. METHODS: In a cohort of 100 middle-aged adults with childhood-onset T1D (aged 49.2 ± 7.0 years, 50F/50M), we assessed cross-sectional associations of DPN, severity of white matter hyperintensities (WMH; Fazekas score), and regional gray matter volume (GMV) with gait speed. Associations were tested separately and combined in linear regression models adjusted for diabetes duration and locomotor risk factors. RESULTS: Average gait speed was 1.3 m/s, with 52% of participants walking below the age-appropriate range of 1.3-1.5 m/s. In separate models, higher WMH severity (ß = -0.27, p = 0.01) and smaller caudate GMV (ß = -0.21, p = 0.04), but not DPN (ß = -0.20, p = 0.08) were associated with slower gait speed. When combined, only WMH severity remained significant (ß = -0.22, p = 0.04). CONCLUSIONS: More than half of participants walked more slowly than expected based on age. Gait speed was slower among those with more severe WMH independent of locomotor risk factors. Gait slowing in middle-aged persons with T1D may reflect brain changes, and thus, deserve further attention.

Differences in Alzheimer's Disease and Related Dementias Pathology Among African American and Hispanic Women: A Qualitative Literature Review of Biomarker Studies.

INTRODUCTION: The 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: Few 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.

Characterization of point-spread function specification error on Geometric Transfer Matrix partial volume correction in [11C]PiB amyloid imaging.

PURPOSE: Partial-volume correction (PVC) using the Geometric Transfer Matrix (GTM) method is used in positron emission tomography (PET) to compensate for the effects of spatial resolution on quantitation. We evaluate the effect of misspecification of scanner point-spread function (PSF) on GTM results in amyloid imaging, including the effect on amyloid status classification (positive or negative). METHODS: Twenty-nine subjects with Pittsburgh Compound B ([11C]PiB) PET and structural T1 MR imaging were analyzed. FreeSurfer 5.3 (FS) was used to parcellate MR images into regions-of-interest (ROIs) that were used to extract radioactivity concentration values from the PET images. GTM PVC was performed using our "standard" PSF parameterization [3D Gaussian, full-width at half-maximum (w) of approximately 5 mm]. Additional GTM PVC was performed with "incorrect" parameterizations, taken around the correct value. The result is a set of regional activity values for each of the GTM applications. For each case, activity values from various ROIs were combined and normalized to produce standardized uptake value ratios (SUVRs) for nine standard [11C]PiB quantitation ROIs and a global region. GTM operating-point characteristics were determined from the slope of apparent SUVR versus w curves. RESULTS: Errors in specification of w on the order of 1 mm (3D) mainly produce only modest errors of up to a few percent. An exception was the anterior ventral striatum in which fractional errors of up to 0.29 per millimeter (3D) of error in w were observed. CONCLUSION: While this study does not address all the issues regarding the quantitative strengths and weakness of GTM PVC, we find that with reasonable caution, the unavoidable inaccuracies associated with PSF specification do not preclude its use in amyloid quantitation.

Imaging beta-amyloid (Aß) burden in the brains of middle-aged individuals with alcohol-use disorders: a [11C]PIB PET study.

No in vivo human studies have examined the prevalence of Alzheimer's disease (AD) neuropathology in individuals with alcohol-use disorder (AUD), although recent research suggests that a relationship between the two exists. Therefore, this study used Pittsburgh Compound-B ([11C]PiB) PET imaging to test the hypothesis that AUD is associated with greater brain amyloid (Aß) burden in middle-aged adults compared to healthy controls. Twenty healthy participants (14M and 6F) and 19 individuals with AUD (15M and 4F), all aged 40-65 years, underwent clinical assessment, MRI, neurocognitive testing, and positron emission tomography (PET) imaging. Global [11C]PiB standard uptake value ratios (SUVRs), cortical thickness, gray matter volumes (GMVs), and neurocognitive function in subjects with AUD were compared to healthy controls. These measures were selected because they are considered markers of risk for future AD and other types of neurocognitive dysfunction. The results of this study showed no significant differences in % global Aß positivity or subthreshold Aß loads between AUD and controls. However, relative to controls, we observed a significant 6.1% lower cortical thickness in both AD-signature regions and in regions not typically associated with AD, lower GMV in the hippocampus, and lower performance on tests of attention as well as immediate and delayed memory in individuals with AUD. This suggest that Aß accumulation is not greater in middle-aged individuals with AUD. However, other markers of neurodegeneration, such as impaired memory, cortical thinning, and reduced hippocampal GMV, are present. Further studies are needed to elucidate the patterns and temporal staging of AUD-related pathophysiology and cognitive impairment. Imaging ß-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer's disease; Registration Number: NCT03746366 .

Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach.

BACKGROUND: Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one ß-amyloid (Aß) 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 Aß 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 Aß 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.

Influence of apolipoprotein-E genotype on brain amyloid load and longitudinal trajectories.

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aß load and longitudinal Aß trajectories, [11C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial [11C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aß burden and an earlier age of onset of Aß positivity, whereas APOE-ε2 appeared to have modest protective effects against Aß. APOE class did not predict rates of Aß accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aß positivity, although it is likely that other genetic, environmental, and lifestyle factors are important.