Christina Caso

Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease

Importance Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. Objective To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18–labeled AV-1451 ([18F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. Design, Setting, and Participants This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [18F]AV-1451 PET imaging to measure tau burden, carbon 11–labeled Pittsburgh Compound B ([11C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Main Outcomes and Measures Tau burden, amyloid burden, and cortical thickness. Results In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [18F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [18F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = –0.82; P < .001; r = –0.70; P < .001; r = –0.58; P < .001; and 3 patients with nonamnesic Alzheimer disease, r = –0.51; P < .001; r = –0.63; P < .001; r = –0.70; P < .001), but not of [11C]PiB binding. Conclusions and Relevance These findings provide further in vivo evidence that distribution of the [18F]AV-1451 signal as seen on results of PET imaging is a valid marker of clinical symptoms and neurodegeneration. By localizing and quantifying hyperphosphorylated tau in vivo, results of tau PET imaging will likely serve as a key biomarker that links a specific type of molecular Alzheimer disease neuropathologic condition with clinically significant neurodegeneration, which will likely catalyze additional efforts to develop disease-modifying therapeutics.

Atrophy in distinct corticolimbic networks subserving social-affective behavior in semantic-variant primary progressive aphasia

OBJECTIVE : Semantic-variant Primary Progressive Aphasia(svPPA) is a neurodegenerative disorder with core impairments in semantic memory. Although many svPPA patients also exhibit symptoms involving social-emotional behavior, these have received relatively little study. We investigated atrophy in large-scale brain networks subserving social-emotional behaviors in svPPA compared to controls. BACKGROUND : We previously defined three social-emotional brain networks in healthy subjects. The perception network guiding detection/interpretation of social sensory cues includes the fusiform gyrus, ventral temporal pole, superior temporal sulcus and lateral orbitofrontal cortex. The affiliation network facilitating prosocial behaviors includes the ventromedial prefrontal, subgenual and rostral anterior cingulate cortices, dorsal temporal pole, hippocampus, parahippocampus, entorhinal cortex and nucleus accumbens. The aversion network mediating avoidant behaviors includes the insula, caudal anterior cingulate cortex and putamen. These networks are linked to amygdalar subregions. We hypothesized that these three networks would exhibit atrophy in svPPA and relate to socioemotional impairment. DESIGN/METHODS : Seventeen svPPA subjects and thirty age-and-gender matched controls were studied. T1-weighted MPRAGE MRI scans were acquired, and FreeSurfer software was used to process data and extract cortical thickness or volumetric data across a priori regions-of-interest. Findings were statistically significant at p≤0.005 to correct for multiple comparisons. The types and severity of social symptoms were rated using the Social Impairment Rating Scale (SIRS). RESULTS : svPPA subjects showed left-lateralized perception(z-score=-4.729; p<0.0001) and affiliation(z-score=-3.483; p=0.0005) network atrophy. Trends toward bilateral amygdala and right perception network atrophy were also observed. Left affiliation network atrophy correlated with SIRS socioemotional detachment sub-scores(r=0.56; p=0.037). The aversion network and control networks (mentalizing and mirror networks) did not show statistically significant atrophy. CONCLUSIONS : svPPA patients demonstrated left-lateralized perception and affiliation network atrophy which may provide the biological basis for social-emotional deficits in these patients. Future symptom-specific analyses may further clarify these brain-behavior relationships. Study Supported by: R21 NS077059, R21 MH097094, and R25 NS065743-05S1. Disclosure: Dr. Perez has nothing to disclose. Dr. Makaretz has nothing to disclose. Dr. Caso has nothing to disclose. Dr. Stepanovic has nothing to disclose. Dr. Brickhouse has nothing to disclose. Dr. Quimby has nothing to disclose. Dr. Hochberg has nothing to disclose. Dr. Xia has nothing to disclose. Dr. Dickerson has received personal compensation for activities with Pfizer, Inc., En Vivo, and Merck.