Karl A. Friedrichsen

Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease

PET imaging of pathological tau correlates more closely with Alzheimer’s disease–related cognitive impairment than does imaging of β-amyloid. A window into Alzheimer’s disease Alzheimer’s disease is pathologically defined by the accumulation of β-amyloid (Aβ) plaques and tau tangles. The cognitive and pathological correlates of Aβ deposition have been well studied owing to the availability of PET imaging ligands. Using newly available tau imaging agents, Brier et al. now explore relationships among tau pathology and Aβ with PET imaging, cerebrospinal fluid measures of disease, and cognition. Overall, tau imaging provided a more robust predictor of disease status than did Aβ imaging. Thus, whereas Aβ imaging provides a good marker for early disease state, tau imaging is a more robust predictor of disease progression. Alzheimer’s disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between β-Amyloid and Tauopathy

IMPORTANCE In vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD. OBJECTIVE To evaluate the usefulness of [18F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among β-amyloid (Aβ), tau, and volume loss. DESIGN, SETTING, AND PARTICIPANTS An imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, >0) were included. MAIN OUTCOMES AND MEASURES Standardized uptake value ratio (SUVR) of [18F]-AV-1451 in the hippocampus and a priori-defined AD cortical signature regions, cerebrospinal fluid Aβ42, hippocampal volume, and AD signature cortical thickness. RESULTS Of the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [18F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [18F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Aβ42-positive (Aβ+) AD from cerebrospinal fluid Aβ42-negative (Aβ-) CN participants. This same cutoff also divided Aβ+ CN participants into low vs high tau groups. Moreover, the presence of Aβ+ was associated with an elevated [18F]-AV-1451 SUVR in AD cortical signature regions (Aβ+ participants: mean [SD], 1.3 [0.3]; Aβ- participants: 1.1 [0.1]; F = 4.3, P = .04) but not in the hippocampus. The presence of Aβ+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [18F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [18F]-AV-1451 SUVR volumetric association was modified by Aβ status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [18F]-AV-1451 SUVR and volume was seen in Aβ+ participants (R2 = 0.55; P < .001) but not Aβ- (R2 = 0; P = .97) participants. CONCLUSIONS AND RELEVANCE Use of [18F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. β-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Aβ, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD.

Partial volume correction in quantitative amyloid imaging.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition.

The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging

The two primary molecular pathologies in Alzheimers disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimers disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.

Neuropathologic assessment of participants in two multi-center longitudinal observational studies: The Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late‐onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN‐NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (eight), Australia (three), UK (one) and Germany (two). By 2014, 41 ADNI and 24 DIAN autopsies (involving nine participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform and state‐of‐the‐art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final “gold standard” neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

Abstract Utilizing [18F]‐AV‐1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data‐driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]‐AV‐1451 binding. 84 cognitively normal participants who had undergone AV‐1451 PET imaging were used in a sparse k‐means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest‐weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV‐1451 uptake. We propose an AV‐1451 SUVR cut‐off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data‐derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by &bgr;‐amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and &bgr;‐amyloid PET imaging in a diseased population. HighlightsAV‐1451 binding in four key regions identifies tau‐positive individuals with preclinical AD.The SUVR cutoff for high and low tau PET is 1.25.Increased tau PET correlates with early cognitive impairment, and relates to &bgr;‐amyloid burden in preclinical AD individuals.The spatial pattern of AV‐1451 uptake in preclinical AD is more widespread than predicted by pathological staging.

Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group

Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimers disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C‐Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET.

CLINICAL RISK RELATED TO CEREBRAL MICROHEMORRHAGES IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: LONGITUDINAL RESULTS FROM THE DIAN STUDY

IC-P-057 CLINICAL RISK RELATED TO CEREBRAL MICROHEMORRHAGES IN AUTOSOMAL DOMINANTALZHEIMER’S DISEASE: LONGITUDINAL RESULTS FROM THE DIAN STUDY Nelly Joseph-Mathurin, Kejal Kantarci, Clifford R. Jack Jr., John M. Ringman, Stephen Salloway, Eric McDade, David Clifford, Tyler Blazey, Karl A. Friedrichsen, Yi Su, Brian A. Gordon, Russ C. Hornbeck, Susan Mills, Beau M. Ances, Marcus E. Raichle, Daniel S. Marcus, Nigel J. Cairns, Chengjie Xiong, Carlos Cruchaga, Alison Goate, Virginia Buckles, Katrina L. Paumier, John C. Morris, Randall J. Bateman, Tammie L. S. Benzinger and Dominantly Inherited Alzheimer Network, Washington University School of Medicine, St. Louis, MO, USA; Mayo Clinic, Rochester, MN, USA; Mayo Clinic College of Medicine, Rochester, MN, USA; University of Southern California, Los Angeles, CA, USA; Alpert Medical School of Brown University, Providence, RI, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA. Contact e-mail: mathurinn@npg.wustl.edu

NEURONAL INJURY AND DEGENERATION EVALUATED WITH IMAGING AND CSF BIOMARKERS IN AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE: RESULTS FROM THE DIAN STUDY

plete work-ups were differently represented for the two diagnoses. No statistically significant change emerged in diagnosis, diagnostic confidence or clinical management between complete, intermediate or incomplete assessments (Table). Stratifying patients for etiopathology (AD-FTD) or clinical severity (MCI-dementia) led to the same results. Conclusions:Collection of additional core bio-markers does not seem to affect the incremental value of amyloid-PET in naturalistic clinical setting. The clinicians combinations and use of instrumental examination needs to be better understood and elucidated in view of the definition of an evidence-based diagnostic algorithm.