Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases.

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aß). 18F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aß, but positive tau positron emission tomography (PET) findings. Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aß (18F-NAV4694) and tau (18F-MK6240) PET scans were included. Centiloid <25 defined negative Aß PET (Aß-). The presence of neocortical tau was defined quantitatively and visually. Results: Aß- PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2, and MAPT genes did not identify relevant functional mutations. Discussion: Discordant cases were infrequent (1.4% of all Aß- participants). In these cases, the Aß PET ligand may not be detecting the Aß that is present.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-ß positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

Assessing Reactive Astrogliosis with 18F-SMBT-1 Across the Alzheimer Disease Spectrum.

A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1) is a novel 18F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18F-SMBT-1 PET regional binding in 77 volunteers (76 ± 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-ß [Aß]-negative [Aß-] and 13 Aß-positive [Aß+]), 12 who had mild cognitive impairment (9 Aß- and 3 Aß+), and 8 who had AD dementia (6 Aß+ and 2 Aß-). All participants also underwent Aß and tau PET imaging, 3-T MRI, and neuropsychologic evaluation. Tau imaging results were expressed in SUV ratios using the cerebellar cortex as a reference region, whereas Aß burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18F-SMBT-1 yielded high-contrast images at steady state (60-80 min after injection). When compared with the Aß- CN group, there were no significant differences in 18F-SMBT-1 binding in the group with Aß- mild cognitive impairment. Conversely, 18F-SMBT-1 binding was significantly higher in several cortical regions in the Aß+ AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18F-SMBT-1 binding was significantly higher in the same regions in the Aß+ CN group as in the Aß- CN group. When all clinical groups were considered together, 18F-SMBT-1 correlated strongly with Aß burden and much less with tau burden. Although in most cortical regions 18F-SMBT-1 did not correlate with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and gray matter volumes, whereas the occipital lobe was directly associated with white matter hyperintensity. 18F-SMBT-1 binding was inversely correlated with Mini Mental State Examination and the Australian Imaging Biomarkers and Lifestyle's Preclinical Alzheimer Cognitive Composite in some neocortical regions such as the frontal cortex, lateral temporal lobe, and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18F-SMBT-1 showed that Aß+ AD patients, but most importantly, Aß+ CN individuals, had significantly higher regional 18F-SMBT-1 binding than Aß- CN individuals. Moreover, in several regions in the brain, 18F-SMBT-1 retention was highly associated with Aß load. These findings suggest that increased 18F-SMBT-1 binding is detectable at the preclinical stages of Aß accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum.

First-in-Humans Evaluation of 18F-SMBT-1, a Novel 18F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis.

Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Methods: Seventy-seven participants-53 who were elderly and cognitively normal, 7 with mild cognitive impairment, 7 with AD, and 10 who were young and cognitively normal-were recruited for the different aspects of the study. Older participants underwent 3-dimensional magnetization-prepared rapid gradient-echo MRI and amyloid-ß, tau, and 18F-SMBT-1 PET. To ascertain 18F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 18F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, 18F-THK5351 studies were also conducted before and after selegiline. Amyloid-ß burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. Results: 18F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate retention in cortical regions, and the lowest retention in cerebellum and white matter, which tightly follows the known regional brain distribution of MAO-B (R 2 = 0.84). More than 85% of 18F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to 18F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. 18F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (∼2.6%/y) similar to the in vitro rates of change (∼1.9%/y). Quantitative and semiquantitative measures of 18F-SMBT-1 binding were strongly associated (R 2 > 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. Conclusion: 18F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, 18F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that 18F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD.

PET Imaging of brain muscarinic receptors with 18F-Fluorobenzyl-Dexetimide: A first in human study.

M1 and M4 muscarinic receptor (mAChR) agonists are under development for the treatment of schizophrenia, Alzheimer's and Parkinson's disease. We performed first-in-human PET imaging of mAChR with 18F-Fluorobenzyl-Dexetimide (FDEX) in 10 healthy participants (29.4±4.3yrs). Four underwent dynamic brain scanning for 240 min, and then six underwent static brain scans at 120 and 160-min post injection of 250 MBq of FDEX. Gjedde-Patlak graphical analysis was applied to determine the influx constant (Ki). Regional tissue ratios (SUVR) were calculated using the cerebellar cortex as the reference region. No adverse events were observed. The tracer showed good brain entry (∼4.2% ID at 5 min) but irreversible distribution kinetics over four hours in regions of high mAChR. Binding was consistent with the distribution of mAChR receptors with striatum > cortex > hippocampus >> thalamus >>> cerebellum with low variance in regional binding between subjects. Ki was 0.42±0.04 in the putamen, 0.27±0.01 in frontal cortex, 0.25±0.02 in the hippocampus and 0.10±0.01 in the thalamus. SUVR at 120 and 240 min. were highly correlated with these Ki values with R2 of 0.91 and 0.99 respectively. FDEX yields high quality brain images with uptake in the known distribution of mAChR with remarkably little variance between normal subjects.

Association of ß-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals.

OBJECTIVE: To determine the effect of ß-amyloid (Aß) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. METHODS: All CN from the Australian Imaging Biomarkers and Lifestyle study with Aß PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aß positive; follow-up 5.3 ± 1.7 years). Aß level was divided using the standardized 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. RESULTS: Aß levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aß, the hazard ratio for progression for moderate Aß was 3.2 (95% confidence interval [CI] 1.3-7.6; p < 0.05), for high was 7.0 (95% CI 3.7-13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p = 0.05), while the high and very high declined substantially (high -0.08 SD/year, p < 0.001; very high -0.35 SD/year, p < 0.001). CONCLUSION: The risk of MCI or dementia over 5 years in older CN is related to Aß level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.

Diagnostic accuracy of imaging brain vesicular monoamine transporter type 2 (VMAT2) in clinically uncertain parkinsonian syndrome (CUPS): a 3-year follow-up study in community patients.

OBJECTIVES: To further validate the diagnostic utility of 18F-AV-133 vesicular monoamine transporter type 2 (VMAT2) positron emission tomography (PET) in patients with clinically uncertain parkinsonian syndromes (CUPS) by comparison to clinical diagnosis at 3 years follow-up. DESIGN, SETTING AND PARTICIPANTS: In a previous study, we reported that 18F-AV-133 PET in community patients with CUPS changed diagnosis and management and increased diagnostic confidence. The current diagnosis of this cohort was obtained from the patient and treating specialist and compared with the diagnosis suggested 3 years earlier by the 18F-AV-133 PET. A second 18F-AV-133 PET was available in those with a discordant or inconclusive final diagnosis. STUDY OUTCOME MEASURES: The primary end point was the proportion of patients who had a follow-up clinical diagnosis, which was concordant with their initial 18F-AV-133 PET scan. Secondary end points were the proportion of patients who had the same diagnosis at follow-up as that reached after the initial scan and the stability of diagnostic changes made after the first scan. RESULTS: 81 of the 85 patients previously recruited to the CUPS study had follow-up of which 79 had a clinical diagnosis and 2 remained CUPS. The diagnosis was in agreement with the initial 18F-AV-133 PET scan result in 74 cases. Five patients had a discordant diagnosis; one patient with rubral tremor had a severely abnormal scan that had worsened when rescanned; four cases with normal initial and repeat scans had a clinical diagnosis of Parkinson's disease. Two patients with suspected genetic disorders remained classified as CUPS and both had normal scans. In the 24 CUPS cohort patients where 18F-AV-133 PET initially changed diagnosis, this change was supported by follow-up diagnosis in all but the one rubral tremor case. CONCLUSION: 18F-AV-133 PET is a useful tool in improving diagnostic accuracy in CUPS providing results and diagnostic changes that remain robust after 3 years follow-up.