Purpose Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear. Methods Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [18F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Results The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.

Introduction We evaluated a new Simoa plasma assay for phosphorylated tau (P‐tau) at aa217 enhanced by additional p‐tau sites (p217+tau). Methods Plasma p217+tau levels were compared to 18 F‐NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18 F‐MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results Compared to Aβ− CU, the plasma levels of p217+tau increased 2‐fold in Aβ+ CU and 3.5‐fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVR MT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Discussion Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.

Background: Neuroinflammatory reaction in Alzheimer's disease (AD) brains involves reactive astrocytes which overexpress monoamine oxidase-B (MAO-B). 18 F-SMBT-1 is a novel F-18 PET tracer highly selective for MAO-B. We characterized the clinical performance of 18 F-SMBT-1 PET across the Alzheimer's disease (AD) continuum as a potential surrogate marker of reactive astrogliosis Methods: We assessed 18 F-SMBT-1 PET regional binding in 77 volunteers (76±5.5 y.o.; 41F/36M) across the AD continuum: 57 cognitively unimpaired controls (CN, 44 A-& 13 A+), 12 mild cognitively impaired (MCI, 9 A-& 3 A+), and 8 AD dementia patients (6 A+ and 2 A-). All participants also underwent A and tau PET imaging, 3T MRI and neuropsychological evaluation. Tau imaging results were expressed in standard uptake value ratios (SUVR) using the cerebellar cortex as reference region, while A burden was expressed in Centiloids. 18 F-SMBT-1 outcomes were expressed as SUVR using the subcortical white matter as reference region.Results: 18 F-SMBT-1 yielded high contrast images at steady state (60-80 min after injection). When compared to A-CN, there were no significant differences in 18 F-SMBT-1 binding in the A-MCI group.Conversely, 18 F-SMBT-1 binding was significantly higher in several cortical regions in the A+AD group, but also was significantly lower in mesial temporal and basal ganglia. Most importantly, 18 F-SMBT-1 binding was significantly higher in the same regions in A+CN when compared to A-CN. When all clinical groups were considered together, 18 F-SMBT-1 was highly correlated with A burden, and much less with tau burden. While in most cortical regions 18 F-SMBT-1 was not correlated with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and grey matter volumes, while the occipital lobe was directly associated with white matter hyperintensities. 18 F-SMBT-1 binding was inversely correlated with MMSE and AIBL PACC in some neocortical regions such as the frontal cortex, lateral temporal and supramarginal gyrus.Conclusions: Cross-sectional human PET studies with 18 F-SMBT-1, showed that A+AD, but most importantly, A+CN have significantly higher regional 18 F-SMBT-1 binding than A-CN. Moreover, in several regions in the brain, 18 F-SMBT-1 retention was highly associated with A load. These findings suggest that increased 18 F-SMBT-1 binding is detectable at the preclinical stages of A accumulation, providing strong support for its use as surrogate marker of astrogliosis in the AD continuum.

Background: Reactive gliosis changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer's disease (AD). Reactive astrocytes overexpress monoamine oxidase-B (MAO-B). We characterized the clinical performance of 18 F-SMBT-1, a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis.Methods: Seventy-seven participants -53 controls (CN), 7 mild cognitively impaired (MCI), 7 AD patients, and 10 young controls (YCN)-were recruited for the different aspects of the study. Older participants underwent 3D-MPRAGE MRI and A, tau, and 18 F-SMBT-1 imaging with PET. To ascertain 18 F-SMBT-1 selectivity to MAO-B, 9 participants underwent two 18 F-SMBT-1 scans, before and after receiving 5mg selegiline twice daily for 5 days. To compare selectivity, 18 F-THK5351 studies were also conducted before and after selegiline. A burden was expressed in Centiloids. 18 F-SMBT-1 outcomes were expressed as standard uptake value, as well as tissue ratios and binding parameters using the subcortical white matter as reference region.Results: 18 F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate in cortical regions, and lowest in cerebellum and white matter which tightly follows the known regional brain distribution of MAO-B (R 2 =0.84). More than 85% of 18 F-SMBT-1 signal was blocked by selegiline across the brain and, in contrast to 18 F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low non-specific binding. 18 F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (~2.6%/yr), similar to the in vitro rates of change (~1.9%/yr). Quantitative and semiquantitative measures of 18 F-SMBT-1 binding were highly associated (R 2 >0.94), suggesting a simplified tissue ratio approach could be used to generate outcome measures.Conclusions: 18 F-SMBT-1 is a highly selective MAO-B tracer, with low non-specific binding, high entry into the brain and displaying reversible kinetics. Moreover, 18 F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting 18 F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18 F-SMBT-1 will require examination of a much larger series, including participants with MCI and AD.

Background and Purpose— The computed tomography angiographic spot sign refers to contrast leakage within intracerebral hemorrhage (ICH). It has been proposed as a surrogate radiological marker for ICH growth. We conducted a meta-analysis to study the accuracy of the spot sign for predicting ICH growth and mortality. Methods— PubMed, Medline, conference proceedings, and article references in English up to June 2017 were searched for studies reporting “computed tomography angiography” and “spot sign” or “intracerebral hemorrhage” and “spot sign.” Each study was ranked on 27 criteria resulting in a quality rating score. Bivariate random effect meta-analysis was used to calculate positive and negative likelihood ratios and area under summary receiver operating characteristics curve for ICH growth and mortality. Hematoma growth was defined using the change in ≥6 mL or ≥33% increase in volume. Results— There were 26 studies describing 5085 patients, including 15 studies not used in previous meta-analyses. Positive likelihood ratio and negative likelihood ratio for ICH growth were 4.85 (95% CI, 3.85–6.02; I 2 =76.1%) and 0.49 (95% CI, 0.40–0.58) and mortality were 4.65 (95% CI, 3.67–5.90) and 0.55 (95% CI, 0.40–0.69), respectively. For ICH growth, the pooled sensitivity was 0.57 (95% CI, 0.49–0.64) and pooled false positive rate was 0.12 (95% CI, 0.09–0.14). The post-test probability of ICH growth was 0.57. The area under the curve for ICH growth and mortality was 0.86 and 0.87 (CIs are not provided in bivariate method). Meta-regression showed sensitivity of the test to decline significantly with subsequent year of publication (β=−0.148; 95% CI, −0.295 to −0.001; P =0.05). Higher quality assessment is associated with lower false positive rate (β=−0.074; 95% CI, −0.126 to −0.022; P =0.006). Conclusions— The high area under the curve potentially suggests that the spot sign can predict hematoma growth and mortality. Caution is recommended in its application given the heterogeneity across studies, which is appropriate given the data.