Neuroimmune signaling across the peripheral-vascular-glial axis is increasingly recognized as a driver of both age-related brain vulnerability and the earliest stages of neurodegenerative disease, including Alzheimer disease. Evaluating this axis in vivo remains challenging due to limited neuroinflammatory imaging biomarkers. We utilized [11C]CS1P1 positron emission tomography (PET) to quantify sphingosine-1-phosphate receptor 1 (S1PR1) availability alongside plasma proteomics in 42 cognitively normal individuals (age 21-82). Through differential abundance analysis and structural equation modeling (SEM), we identified a multi-compartment neuroimmune cascade linking peripheral T-cell activation (CD40LG), vascular endothelial disruption (ICAM1/TEK), central S1PR1 upregulation, and reactive astrogliosis (GFAP). Mediation analysis estimated this S1PR1 axis accounts for 25.5% of the total effect of CD40LG on GFAP. This cascade appears coupled to the astrocytic immune response and is exacerbated by underlying amyloid-beta pathology. These findings suggest [11C]CS1P1 may serve as an in vivo tool for evaluating peripheral-to-central immune crosstalk.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.

BACKGROUND AND PURPOSE:Sphingosine-1-phosphate receptor 1 (S1PR1) is a key regulator of neuroinflammation and plays a crucial role in multiple neurodegenerative diseases. [11C]CS1P1 is a novel PET tracer for measuring expression levels of S1PR1 in humans. Before widespread application, its quantification must be established and evaluated in healthy young and old adults through characterization of binding topographies, kinetics, and tracer metabolism rates. MATERIALS AND METHODS:We acquired dynamic [11C]CS1P1 emission data from 29 healthy controls and investigated the topography of [11C]CS1P1 uptake, radio-labeled metabolites of the tracer, an image-derived input function estimation, and tissue compartment modeling. RESULTS:The image-derived input function approximated the arterially sampled input function. Further, radio-labeled metabolites of the tracer accumulated linearly throughout the scan and demonstrated consistency across participants. A 2-tissue compartment model fitted the observed emission data well, consistent with previously reported nonhuman primate studies. Kinetic modeling using the image-derived input functions, corrected by population estimates of tracer metabolism, provided a good fit for tissue activity curves. Graphical Logan analysis reliably estimated volume of distribution (Vt), and Vt closely reproduced S1PR1 distribution in the brain. CONCLUSIONS:In this study, we have established a quantitative 11C]CS1P1 PET processing approach by using a 2-tissue compartment model and imaging-derived input function with population metabolite correction. [11C]CS1P1 PET reflects S1PR1 topography and supports its use for investigating neuroinflammation in humans.

Autosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta-amyloid (Aβ) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics. Omics approaches can inform NVU changes and their disease associations. CSF proteomic data using the Somalogic ® platform was generated from 485 participants in the DIAN study, who also had PiB-PET and MRI assessing Aβ burden, white matter hyperintensity (WMH), and cerebral microhemorrhage (CMH). From previously published AD studies, we identified 33 NVU-associated proteins with corresponding Somalogic aptamers (Figure 1). We used Principal Component Analysis (PCA) on participants with complete data (n=262, 166 mutation-carriers and 96 non-carriers) to find groups of proteins associated with mutation status and disease stage as measured with estimated year to symptom onset (EYO), PiB-PET, and clinical status. Linear-mixed effect models and two-part zero-inflated negative binomial mixed models further evaluated the link between significant principal components (PCs) and WMH and CMH, respectively. Models accounted for age, APOE-e4 status, sex, and education. The first ten PCs explained >60% of the variance in NVU-related protein levels (Figure 2A) with only PC5 (4.8%) associated with mutation*EYO, suggesting relationship with ADAD-specific disease progression (***p<0.0001, Figure 2B). While asymptomatic PiB-negative individuals were not significantly different from non-carriers, asymptomatic PiB-positive individuals had higher PC5 scores than non-carriers and symptomatic individuals scored still higher (**p<0.005, ***p<0.0001, Figure 2C). The main proteins composing PC5 were: neurofilament light-chain, angiopoietin-2, SMOC1, LRP1, E-selectin, and sTREM2, suggesting strong association with proinflammatory glial response from neuronal injury (Figure 2D). PC5 was also associated with WMH volumes (*p<0.05, Figure 3A) and with CMH count in participants with CMH (**p<0.005, Figure 3B). This PCA approach indicates that some groups of NVU-associated proteins are related with mutation status and disease stage, and that they are differentially associated with features of ADAD such as white matter integrity as measured by WMH volume. Weighted Correlation Network Analysis will be of interest to further understand these associations. Funding : K01AG080123, RF1-AG044546, UF1AG032438

INTRODUCTION:Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS:Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS:Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION:We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS:Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing input distributions to VG3 dendrite responses, we show that VG3 dendrites have a short functional length constant that likely depends on inhibitory shunting. This model predicts that RGCs that extend dendrites into the middle layers of the inner plexiform encounter VG3 dendrites whose responses vary according to the local bipolar cell response type.

Correlated light and electron microscopy (CLEM) can be used to combine functional and molecular characterizations of neurons with detailed anatomical maps of their synaptic organization. Here we describe a multiresolution approach to CLEM (mrCLEM) that efficiently targets electron microscopy (EM) imaging to optically characterized cells while maintaining optimal tissue preparation for high-throughput EM reconstruction. This approach hinges on the ease with which arrays of sections collected on a solid substrate can be repeatedly imaged at different scales using scanning electron microscopy. We match this multiresolution EM imaging with multiresolution confocal mapping of the aldehyde-fixed tissue. Features visible in lower resolution EM correspond well to features visible in densely labeled optical maps of fixed tissue. Iterative feature matching, starting with gross anatomical correspondences and ending with subcellular structure, can then be used to target high-resolution EM image acquisition and annotation to cells of interest. To demonstrate this technique and range of images used to link live optical imaging to EM reconstructions, we provide a walkthrough of a mouse retinal light to EM experiment as well as some examples from mouse brain slices.

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem—commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.

Automated tape collection of ultrathin sections was developed to facilitate the collection of large numbers of sections (Hayworth et al., 2014; Schalek et al., 2012). Scanning electron microscopy of ultrathin sections preserved on the stable substrate of collection tape and silicon wafers also lends itself to the reimaging of tissue at multiple resolutions. Multi-resolution serial section SEM can be used to link 3D ultrastructure of local circuitry to millimeter-scale axon projections without the need to acquire petabytes of data. Micron-resolution mapping of 3D image volumes can also be readily correlated to 3D optical image volumes, adding functional or molecular information to electron microscopic circuit reconstructions. We use this multi-modal / multi-resolution approach to uncover the synaptic connectivity of mouse retinal amacrine neurons that have been labeled transgenically and functionally characterized with two-photon calcium imaging. Subtype specific promotors were used to transgenically drive the expression of fluorescent proteins in mouse retinal amacrine cells. Light responses to amacrine neurons expressing the calcium indicator GCamp6 were characterized using two-photon live imaging. Retinas were then aldehyde fixed and reimaged with confocal microscopy to generate tissue maps of fluorescent protein expressing cell bodies relative to surrounding cell bodies and blood vessels. Cell bodies and blood vessels could be identified using aldehyde background fluorescence. Additional tissue reference signal could be generated by labeling nuclei with DAPI and enhancing background signal with Sulfarhodamine. After optical mapping, tissue was fixed in additional glutaraldehyde and stained using double layered osmium, uranyl acetate and lead aspartate. Retina tissue blocks ( >1mm^2) were cut into ~1500 ultrathin en face sections

INTRODUCTION:18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's 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. METHODS:FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. RESULTS:Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. DISCUSSION:Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.

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 β-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 β-amyloid PET imaging in a diseased population.

Clinical trials of some anti-amyloid treatments have shown increased risks of cerebral microhemorrhages (MCHs) in individuals with Alzheimer disease. These are detectable with gradient-echo (GRE) MR imaging sequences and are part of the constellation of findings defined as amyloid-related imaging abnormalities (ARIA) for which the FDA has recommended monitoring during trials. The presence of 5 or more MCHs has been suggested as a criteria of exclusion from trials. Our aim was to investigate the prevalence of MCHs and their evolution with the disease process in individuals at risk for autosomal dominant Alzheimer disease (ADAD). Non-mutation carriers (NC, n=58, age=40.6±9.7years) and mutation carriers (MC, n=108, age=41.6±9.5years) underwent GRE MR sequences to detect MCH. All individuals had at least 2 imaging visits spaced by 1.9±1.1years. MCH number, siderosis, and macroscopic hemorrhages were visually quantified on each scan. Longitudinal analysis were performed to characterize the pattern of progression of MCHs with the mutation type, estimated year to symptom onset (EYO) for asymptomatic participants, and dementia using clinical dementia rating (CDR). MCH were observed in 19 participants (11%), 18 of whom were MCs (PSEN1=13, PSEN2=1 and APP=4). For all participants with MCH at baseline, the rate of increase per year was 0 for NCs and 0.88±3.66 for MCs overall, but 7.05±3.04 MCHs per year for 13 participants with 2 MCHs or more at baseline (mutation type was unassociated with rate of increase, (Figure 1z).). In MCs, the increased rate per year was higher once past the estimated symptom onset (EYO>0, p<0.0005) and when they were cognitively impaired (CDR>0, p<0.005) (Figure 2). Siderosis was detected in participants with (n=3) or without (n=2) MCH. Macrohemorrhages were present only in 2 participants with MCHs within the APP mutation type and could not be directly correlated with the presence of MCHs.

18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neurodegeneration in Alzheimer's disease (AD). Here, we evaluate the utility of surrogate perfusion measurements obtained from models of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neurodegeneration and to potentially decrease participant burden. FDG and full dynamic PiB imaging were obtained from 110 participants from the Dominantly Inherited Alzheimer Network (DIAN), including 45 non-carriers (NC, 38.2±10.1 years) and 65 mutation-carriers (MC, 39.8±12.0 years). Two surrogate perfusion measurements were obtained from the PiB scan. The first measurement was SUVRs of early frames of PiB (ePiB, 1 to 9 min) normalized to the brainstem. The second measurement was the relative tracer influx rate (R1) obtained from kinetic modeling of PiB data, using brainstem as the reference region. Partial volume correction was applied to take into account the atrophic process. Regional cross-sectional analyses were performed to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Nine regions were evaluated, including the precuneus and the inferior parietal cortex, known to be greatly affected by hypometabolism. Metabolism and perfusion images were spatially highly correlated, showing decreased signal in similar regions (Figure 1). Across all participants, the R1 values were better correlated to FDG than ePiB was (e.g. r=0.52, p<0.0001 and r=0.54, p<0.0001 for R1 vs. FDG in the inferior parietal and the precuneus, respectively, and r=0.28, p<0.005 and r=0.10, n.s. for ePiB vs. FDG in the inferior parietal and the precuneus, respectively, Figure 2). Regional R1 values and FDG significantly decreased in the MC vs. NC with estimated-year-to-onset (p<0.05 for the inferior parietal) while ePiB did not decrease but increased instead (p<0.05 for the inferior parietal) (Figure 3). Within the MC, R1 values and FDG significantly decreased with dementia severity (p<0.05 for the inferior parietal) while ePiB had no relationship with dementia for any regions.

18F-AV-1451 is a PET tracer used for the evaluation of neurofibrillary tangle pathology in vivo. The objective of the current work is to examine the patterns of AV1451 uptake in autosomal dominant Alzheimer’s disease (AD), compared to late-onset (LOAD) Alzheimer’s disease. Participants in the Dominantly Inherited Alzheimer Network (DIAN) undergoing imaging visits at Washington University during 2015 and 2016 underwent AV1451 tau PET imaging, in addition to MRI and 11C-PiB amyloid and 18F-FDG PET. Comparisons are made between the uptake patterns between the PET tracers in 11 participants. Additionally the patterns of amyloid and tau in DIAN participants are compared to a cohort of 63 participants in a study of LOAD. Standardized uptake value ratios (SUVRs) were obtained from the 80-100 minute post-injection window, using whole cerebellum as the reference region. Patterns of tau deposition within the temporal lobe are similar for cognitively impaired participants from DIAN compared to sporadic AD. However, DIAN participants with only mild impairment (Clinical Dementia Rating (CDR) = 0.5) have apparently increased uptake in the precuneus, parietal lobe, and frontal lobes compared to sporadic AD (Figure 1). Glucose hypometabolism in symptomatic DIAN participants is confined to regions of elevated AV1451 uptake (Figure 2). Enrollment is ongoing; additional data is required for full statistical modeling.

The two primary pathologies in Alzheimer disease are the aggregation of beta-amyloid into plaques and of tau into neurofibrillary tangles. Quantifications of these pathologies in vivo have been restricted to cerebrospinal fluid (CSF) assays, and positron emission tomography (PET) using beta-amyloid tracers. The addition of PET tau tracers provides a valuable tool, although the relationships between this tracer to other Alzheimer biomarkers are still unknown. We examined the radioactive [F-18]- AV-1451 positron emission tomography (PET) tracer, a tau ligand, in a population of 41 cognitively normal and 9 demented older adults. All participants underwent a lumbar puncture to assess CSF levels of total tau, p-tau181 and Aβ42. Statistics were run at a voxel-wise level using nonparametric permutation testing implemented within FSL. Initial analyses examined patterns of elevated tau deposition associated with cognitive impairment. Additional analyses related levels of all three CSF biomarkers of pathology to PET tau deposition. All analyses controlled for age and gender. Analyses examining the relationships between PET and CSF measures included the time between imaging and lumbar puncture assessments as an additional covariate. Cognitive impaired individuals (Clinical Dementia Rating >0) had elevated levels of PET tau deposition. This elevation was most prominent in the medial temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices (Figure 1). In the entire cohort, there were significant relationships between all three CSF biomarkers and PET tau deposition (Figure 2), but the strongest relationships were for CSF tau-related markers. Within the cognitively normal cohort (CDR=0) levels of CSF Aβ42, but not t-tau or p-tau181, were associated with elevated PET tau deposition confined primarily to the medial temporal lobe and adjacent neocortical regions (Figure 2).

[This corrects the article DOI: 10.1371/journal.pone.0152082.].

Frontotemporal dementia (FTD) is a neurodegenerative disease, a subset of which is characterized by abnormal accumulation of tau protein. One of the inherited forms of the disease is caused by mutations in the MAPT(microtubule associated protein tau) gene. Positron emission tomography (PET) radiotracers have been developed for detecting tau in vivo (AV-1451) and have been used in studying Alzheimer’s disease and other diseases featuring tauopathy. [18F]-Fluorodeoxyglucose (FDG) is a radiotracer used for evaluating metabolism and has previously shown regional hypometabolism to be a reliable biomarker of FTD and other neurodegenerative conditions. Our current aim is to evaluate the relationship of these two biomarkers in familial FTD, both prior to and after the emergence of symptoms. PET scans (FDG and AV-1451) from two participants with the same MAPT mutation (R406W) were evaluated. One participant was asymptomatic and one symptomatic, as measured with the Clinical Dementia Rating, FTLD Uniform Data Set (UDS), and FTLD Neuropsychological battery. An MRI was acquired, and ROIs were defined by FreeSurfer automated brain segmentation software. The PET data were converted to partial volume corrected Standard Uptake Value Ratio (SUVR) images using whole cerebellum as a reference region. The FDG scans for both participants show hypometabolism in the anterior temporal lobes, with more severe and extensive hypometabolism observed in the symptomatic participant (Fig 1). The AV-1451 scan for the asymptomatic individual showed no observable tau deposition (entorhinal cortex SUVR=0.97), while the symptomatic individual showed significant binding restricted to the anterior temporal lobes (entorhinal cortex SUVR=2.75).

Development of radiotracers for imaging tau protein in vivo holds potential for identifying early biomarkers of diseases featuring tauopathy, such as Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD), even prior to clinical presentation. Our aim is to identify binding topographies and relate them to disease and aging processes. Seventy-one adults (12 with global Clinical Dementia Ratings (CDR) above zero) underwent [F-18]-AV-1451 positron emission tomography (PET). Seven participants were from a familial FTD cohort, six of whom were carriers of MAPT mutations. Regions of interest (ROI) were determined using FreeSurfer. PET data were partial-volume corrected, converted to Standardized Uptake Value Ratios (SUVRs) normalized to whole cerebellum, and averaged across hemispheres. Data from 37 ROIs were entered into a principal component analysis. Sixty-two participants also underwent beta-amyloid PET scans using either Pittsburgh Compound B (PiB) or Florbetapir (AV45) and were categorized as beta-amyloid positive or negative by a mean cortical SUVR cutoff. Three components were identified, accounting for 83% of the binding variance. The first component (61% total variance) had positive loadings in the temporal, parietal, and occipital lobes, both lateral and medial surfaces. Component 2 was almost entirely comprised by the choroid plexus. Component 3 had positive loadings for the medial temporal lobes and negative for the posterior areas of component 1. Component 1 was higher in beta-amyloid positive participants. Component 2 correlated weakly with age. Component 3 was higher in the FTD cohort compared to the AD cohort.

The two primary molecular pathologies in Alzheimer's 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 Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.