Combining cerebrospinal fluid and PI-2620 tau-PET for biomarker-based stratification of Alzheimer's disease and 4R-tauopathies.

INTRODUCTION: Recent advances in biomarker research have improved the diagnosis and monitoring of Alzheimer's disease (AD), but in vivo biomarker-based workflows to assess 4R-tauopathy (4RT) patients are currently missing. We suggest a novel biomarker-based algorithm to characterize AD and 4RTs. METHODS: We cross-sectionally assessed combinations of cerebrospinal fluid measures (CSF p-tau181 and t-tau) and 18F-PI-2620 tau-positron emission tomography (PET) in patients with AD (n = 64), clinically suspected 4RTs (progressive supranuclear palsy or corticobasal syndrome, n = 82) and healthy controls (n = 19). RESULTS: Elevated CSF p-tau181 and cortical 18F-PI-2620 binding was characteristic for AD while normal CSF p-tau181 with elevated subcortical 18F-PI-2620 binding was characteristic for 4RTs. 18F-PI-2620-assessed posterior cortical hypoperfusion could be used as an additional neuronal injury biomarker in AD. DISCUSSION: The specific combination of CSF markers and 18F-PI-2620 tau-PET in disease-specific regions facilitates the biomarker-guided stratification of AD and 4RTs. This has implications for biomarker-aided diagnostic workflows and the advancement in clinical trials. HIGHLIGHTS: Novel biomarker-based algorithm for differentiating AD and 4R-tauopathies. A combination of CSF p-tau181 and 18F-PI-2620 discriminates AD versus 4R tauopathies. Hypoperfusion serves as an additional neuronal injury biomarker in AD.

[Tau Positron Emission Tomography: Applications in Diagnosis and Prognosis of Various Diseases].

Tau positron emission tomography (PET) is a neuroimaging technique that visualizes tau deposition using PET tracers that selectively bind to tau aggregates. Studies have reported the diagnostic and prognostic value of tau PET in Alzheimer's disease and other tauopathies. However, the binding profiles of tau PET drugs vary widely across tauopathies; therefore, an accurate understanding of the disease-specific characteristics is essential for interpretation of tau PET findings. In this review, we discuss the properties of tau-PET agents and their applications in various diseases.

Ligand-Based Virtual Screening as a Path to New Chemotypes for Candidate PET Radioligands for Imaging Tauopathies.

Ligand-based virtual screening (LBVS) has rarely been tested as a method for discovering new structural scaffolds for PET radioligand development. This study used LBVS to discover potential chemotype leads for developing radioligands for PET imaging of tauopathies. ZINC12, a free database of over 12 million commercially available compounds, was searched to discover novel scaffolds based on similarities to four query compounds. Thirteen high-ranking hits were purchased and assayed for their ability to compete against three tritiated radioligands at their distinct binding sites in Alzheimer's disease brain tissue. Three hits were 2-substituted 6-methoxy naphthalenes. Synthetic elaboration of this new chemotype yielded three new ligands (25, 26, and 28) with high affinity for the [3H]6 (flortaucipur) neurofibrillary tangle binding site. Compound 28 showed remarkably high affinity (Ki, 7 nM) and other desirable properties for a candidate PET radioligand, including low topological polar surface area, moderate computed log D, and amenability for labeling with carbon-11. LBVS appears to be uniquely valuable for discovering new chemotypes for candidate PET radioligands.

Flortaucipir PET uncovers relationships between tau and amyloid-ß in primary age-related tauopathy and Alzheimer's disease.

[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-ß. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-ß PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-ß phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-ß phase. Flortaucipir uptake linearly increased with the amyloid-ß phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-ß phase, and were useful for distinguishing different ADNC scores and PART.

Neuroinflammation Parallels 18F-PI-2620 Positron Emission Tomography Patterns in Primary 4-Repeat Tauopathies.

BACKGROUND: Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. OBJECTIVE: We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. METHODS: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. RESULTS: In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (ß = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (ß = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. CONCLUSIONS: Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Distinct biological property of tau in tau-first cognitive proteinopathy: Evidence by longitudinal clinical neuroimaging profiles and compared with late-onset Alzheimer disease.

BACKGROUND: Tau-first cognitive proteinopathy (TCP) denotes a clinical phenotype of Alzheimer disease (AD) showing Florzolotau(18F) positron emission tomography (PET) positivity but a negative amyloid status. AIM: We explored the biological property of tau using longitudinal cognitive and neuroimaging data in TCP and compared with late-onset AD (LOAD). METHOD: We enrolled 56 patients with LOAD, 34 patients with TCP, and 26 cognitive unimpaired controls. All of the participants had historical data of 2 to 4 three-dimensional T1 images and 2 to 6 annual cognitive evaluations over a follow-up period of 7 years. Tau topography was measured using Florzolotau(18F) PET. In the LOAD and TCP groups, we constructed tau or gray matter clusters covarying with the cognitive measurements. We used mediator analysis to explore the regional tau load as predictor, gray matter partitions as mediators, and significant cognitive test scores as outcomes. Longitudinal cognitive decline and cortical thickness degeneration pattern were analyzed using a linear mixed-effects model. RESULTS: The TCP group had longitudinal declines in nonexecutive domains. The deterministic factor predicting the short-term memory score in TCP was the hippocampal volume and not directly via the medial and lateral temporal tau load. These features formed the conceptual differences with LOAD. DISCUSSION: The biological properties of tau and the longitudinal cognitive-imaging trajectory support the conceptual distinction between TCP and LOAD. TCP represents one specific entity featuring salient short-term memory impairment, declines in nonexecutive domains, a slower gray matter degenerative pattern, and a restricted impact of tau.

In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study.

BACKGROUND: Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models. RESULTS: Positron emission tomography imaging using [18F]PM-PBB3 (tau), [18F]florbetapir (amyloid-beta), [18F]SMBT-1 (monoamine oxidase-B), [18F]DPA-714 (translocator protein) and [18F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [18F]PM-PBB3, [18F]SMBT-1, and [18F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [18F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [18F]florbetapir and [18F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [18F]SMBT-1 and [18F]PM-PBB3, [18F]DPA-714 and [18F]PM-PBB3 in rTg4510 mice, and between [18F]florbetapir and [18F]DPA-714 SUVRs in 5 × FAD mice. CONCLUSION: In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease.

TDP-43 Is Associated with Subiculum and Cornu Ammonis 1 Hippocampal Subfield Atrophy in Primary Age-Related Tauopathy.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aß (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [18F]APN-1607 and [18F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

A multimodal clinical diagnostic approach using MRI and 18F-FDG-PET for antemortem diagnosis of TDP-43 in cases with low-intermediate Alzheimer's disease neuropathologic changes and primary age-related tauopathy.

OBJECTIVE: To evaluate the utility of clinical assessment scales for MRI and 18F-FDG-PET as potential in vivo predictive diagnostic tools for TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy in cases with low-intermediate Alzheimer's disease neuropathologic changes (ADNC) and primary age-related tauopathy (PART). METHODS: We conducted a cross-sectional analysis on patients with antemortem MRI and 18F-FDG-PET scans and postmortem diagnosis of low-intermediate ADNC or PART (Braak stage ≤ III; Thal ß-amyloid phase 0-5). We employed visual imaging scales to grade structural changes on MRI and metabolic changes on 18F-FDG-PET and statistically compared demographic and clinicopathological characteristics between TDP-43 positive and negative cases. Independent regression analyses were performed to assess further influences of pathological characteristics on imaging outcomes. Within-reader repeatability and inter-reader reliability were calculated (CI = 0.95). Additional quantitative region-of-interest analyses of MRI gray matter volumes and PET ligand uptake were performed. RESULTS: Of the 64 cases in the study, 20 (31%) were TDP-43 ( +), of which 12 (60%) were female. TDP-43 ( +) cases were more likely to have hippocampal sclerosis (HS) (p = 0.014) and moderate-severe medial temporal lobe atrophy on MRI (p = 0.048). TDP-43( +) cases also showed a trend for less parietal atrophy on MRI (p = 0.086) and more medial temporal lobe hypometabolism on 18F-FDG-PET (p = 0.087) than TDP-43( - ) cases. Regression analysis showed an association between medial temporal hypometabolism and HS (p = 0.0113). ICC values for MRI and PET within one reader were 0.75 and 0.91; across two readers were 0.79 and 0.82. The region-of-interest-based analysis confirmed a significant difference between TDP-43( +) and TDP-43( - ) cases for medial temporal lobe gray matter volume on MRI (p = 0.014) and medial temporal metabolism on PET (p = 0.011). CONCLUSION: Visual inspection of the medial temporal lobe on MRI and FDG-PET may help to predict TDP-43 status in the context of low-intermediate ADNC and PART.

In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies.

Alzheimer's disease (AD) and non-AD tauopathies such as chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are characterized by the abnormal aggregation of three-repeat (3R) and/or four-repeat (4R) tau isoforms. Several tau-PET tracers have been applied for human imaging of AD and non-AD tauopathies including [18F]PI-2620. Our objective is to evaluate [3H]PI-2620 and two promising structural derivatives, [3H]PI-2014 and [3H]F-4, using in vitro saturation assays and competitive binding assays against new chemical entities based on this scaffold in human AD tissues for comparison with PSP, CBD and CTE tissues. Thin section autoradiography was employed to assess specific binding and distribution of [3H]PI-2620 and [3H]F-4 in fresh-frozen human post-mortem AD, PSP, CBD and CTE tissues. Immunohistochemistry was performed for phospho-tau (AT8) and 4R-tau (RD4). Homogenate filtration binding assays were performed for saturation analysis and competitive binding studies against [3H]PI-2620. All compounds bound with high affinity in AD tissue. In PSP tissue [3H]PI-2620 demonstrated the highest affinity (5.3 nM) and in CBD tissue [3H]F-4 bound with the highest affinity (9.4 nM). Over 40 fluorinated derivatives based on PI-2620 and F-4 were screened in AD and PSP tissue. Notably, compound 2 was the most potent derivative in PSP tissue (Ki = 7.3 nM). By autoradiography, [3H]PI-2620 and [3H]F-4 demonstrated positive signals similar in intensity in AD, PSP and CTE tissues that were displaced by homologous blockade. Binding of both radiotracers aligned with immunostaining for 4R-tau. This work demonstrates that [3H]PI-2620 and [3H]F-4 show promise for imaging 4R-tau aggregates in non-AD tauopathies. PI-2620 continues to serve as a structural scaffold for PET radiotracers with higher affinity for non-AD tau over AD tau.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

The spatial extent of tauopathy on [18F]MK-6240 tau PET shows stronger association with cognitive performances than the standard uptake value ratio in Alzheimer's disease.

PURPOSE: [18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer's disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). METHODS: [18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. RESULTS: The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08-0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. CONCLUSIONS: Quantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Synthesizing images of tau pathology from cross-modal neuroimaging using deep learning.

Given the prevalence of dementia and the development of pathology-specific disease-modifying therapies, high-value biomarker strategies to inform medical decision-making are critical. In vivo tau-PET is an ideal target as a biomarker for Alzheimer's disease diagnosis and treatment outcome measure. However, tau-PET is not currently widely accessible to patients compared to other neuroimaging methods. In this study, we present a convolutional neural network (CNN) model that imputes tau-PET images from more widely available cross-modality imaging inputs. Participants (n = 1192) with brain T1-weighted MRI (T1w), fluorodeoxyglucose (FDG)-PET, amyloid-PET and tau-PET were included. We found that a CNN model can impute tau-PET images with high accuracy, the highest being for the FDG-based model followed by amyloid-PET and T1w. In testing implications of artificial intelligence-imputed tau-PET, only the FDG-based model showed a significant improvement of performance in classifying tau positivity and diagnostic groups compared to the original input data, suggesting that application of the model could enhance the utility of the metabolic images. The interpretability experiment revealed that the FDG- and T1w-based models utilized the non-local input from physically remote regions of interest to estimate the tau-PET, but this was not the case for the Pittsburgh compound B-based model. This implies that the model can learn the distinct biological relationship between FDG-PET, T1w and tau-PET from the relationship between amyloid-PET and tau-PET. Our study suggests that extending neuroimaging's use with artificial intelligence to predict protein specific pathologies has great potential to inform emerging care models.

Suspecting Non-Alzheimer's Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images.

BACKGROUND: Alzheimer's disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. OBJECTIVE: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies. METHODS: Sixty-one patients presenting cognitive complaints (age 48-90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n = 30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH). RESULTS: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson's r = -0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism > Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism > Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens. CONCLUSIONS: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens.