Objective Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer’s disease (AD), staging and monitoring of disease progression, and development of disease modifying therapies. Methods We acquired tau positron emission tomography (PET) using 18F T807 (AV1451), and amyloid-β PET using 11C Pittsburgh Compound B (PIB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. Results We found abnormally high cortical 18F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical 18F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal 18F T807 than with mean cortical 11C PIB. Regional 18F T807 was correlated with mean cortical 11C PiB among both impaired and control subjects. Interpretation These findings suggest that 18F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.

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Key Points Question Is cognitive decline associated with amyloid-β or tau tangles accumulation? Findings In this cohort study that included 60 normal older adults with repeated positron emission tomography measures, the rate of tau accumulation in the inferior temporal neocortex was associated with the rate of cognitive decline. Amyloid accumulation was associated with subsequent tau accumulation, and this sequence of successive amyloid and tau changes in neocortex was found to mediate the association of initial amyloid with final cognition, measured 7 years later. Meaning Amyloid positron emission tomography is useful to detect early Alzheimer pathology; repeated tau positron emission tomography is useful to track disease progression.

Tumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.