Biomarkers.

TAU AND AMYLOID CAUSE DISRUPTION IN WHITE MATTER CONNECTIVITY DIFFERENTLY FOR EARLY- AND LATE-ONSET ALZHEIMER'S DISEASE

Small-animal positron emission tomography as a tool for neuropharmacology

Background18F‐Flortaucipir is widely used for positron emission tomography (PET) imaging of Alzheimer’s disease (AD)‐type tau, but its sensitivity in early Braak stages has been questioned, and hippocampal uptake is at least partially confounded by off‐target binding. We investigated associations between antemortem PET uptake and digitally‐quantified tau and TDP‐43 neuropathology.MethodsParticipants (n = 14, Figure 1) included 5 people with no/low AD neuropathologic change (ADNC) at autopsy, 2 intermediate, and 7 high. Clinical diagnoses included normal cognition (n = 2), AD (n = 5), dementia with Lewy bodies (n = 2), Parkinson’s disease dementia (n = 1), corticobasal syndrome (n = 2), and posterior cortical atrophy (n = 2). We used the Automated Segmentation of Hippocampal Subfields T1 MRI pipeline to segment anterior and posterior hippocampus, Brodmann’s areas (BA) 35 (transentorhinal cortex) & 36, and entorhinal cortex. 18F‐Flortaucipir standardized uptake value ratios (SUVRs) were computed relative to inferior cerebellar grey matter and averaged across hemispheres. Postmortem sampling comprised hippocampal subiculum, CA1, CA2, CA3, and dentate gyrus; BA35 and BA36; and entorhinal cortex. FFPE‐brain tissue was immunostained using PHF1 and phospho‐specific TDP‐43 antibodies and digitally imaged. Two different weakly supervised learning algorithms, Wildcat, were trained to identify tau tangles and threads; or somatic and neuritic phosphorylated TDP‐43 (pTDP‐43) inclusions. Each pathology type was quantified by summary statistics on Wildcat heatmaps, averaged over hippocampal subfields; and over BA35/entorhinal cortex (Denning et al., 2024). We computed non‐parametric correlations between SUVRs and pathology measures at a=0.05 with false discovery rate correction.ResultsTangles were associated with SUVRs in BA35/entorhinal cortex (Spearman’s r=0.59, p = 0.029; Figure 2A). The mean hippocampal tangle measure was associated with SUVRs in both anterior (r=0.77, p = 0.002) and posterior (r=0.77, p = 0.002) hippocampus (Figure 2B‐C). Associations between SUVR and tau threads were marginally significant (Figure 2D‐F). In BA35/entorhinal cortex, 9/9 intermediate‐high ADNC cases had SUVRs above an established positivity cutoff of 1.23 (Figure 3). PET SUVRs were not associated with somatic or neuritic pTDP‐43 measures.ConclusionResults suggest 18F‐flortaucipir is sensitive to tau burden in early Braak‐stage regions and primarily reflects neurofibrillary tangles rather than thread‐like tau inclusions.

BackgroundCerebral blood flow (CBF) changes play a pivotal role in the pathogenesis and progression of Alzheimer's disease (AD), but their effects on other pathological processes, such as neurodegeneration and amyloid‐β deposition, are unclear. We investigated the correlations between cerebral perfusion measured with arterial spinal labeling (ASL) and cerebral metabolism and amyloid deposition on positron emission tomography (PET) scans in ADMethodSixty‐four AD patients and 56 cognitively unimpaired controls were included. Cerebral perfusion was indicated by the expression of AD‐related perfusion pattern (ADRP), global CBF and the relative value of regional CBF. The standardized uptake value ratio (SUVR) of regions of interest (ROIs) was calculated for 18F‐fluorodeoxyglucose (FDG)‐PET and 11C‐Pittsburgh Compound B (PiB)‐PET images in AD.ResultThe subject expression score of ADRP showed strong negative correlations with FDG SUVR in all ROIs and a positive correlation with PiB SUVR in temporal. FDG SUVR in some ROIs were also positively correlated with global CBF and relatively regional CBF in the temporoparietal cortex, precuneus and posterior cingulate, and negatively correlated with relatively regional CBF in the thalamus and pre‐ and postcentral regions. The PiB SUVR of the ROIs were negatively correlated with the relatively regional CBF in the left inferior parietal region and were positively correlated with the relatively regional CBF in the right thalamus and left precentral regions.ConclusionCBF was significantly correlated with hypometabolism and amyloid deposition in AD.

BackgroundGosuranemab is a humanized monoclonal antibody that is hypothesized to neutralize extracellular tau and prevent the trans‐neuronal propagation of tau pathology across the brain. The TANGO study is an ongoing randomized, placebo‐controlled, global Phase 2 study evaluating safety and clinical efficacy of gosuranemab in individuals diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild AD dementia. The TANGO study included two biomarker sub‐studies: cerebrospinal fluid (CSF) sub‐study and Tau positron emission tomography (PET) sub‐study; the baseline characteristics of the Tau PET sub‐study are described below.MethodTANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI or mild AD, who were amyloid positive as assessed by amyloid PET or CSF testing. Approximately 350 patients enrolled in the longitudinal 18F‐MK‐6240 Tau PET sub‐study. Randomization was stratified by biomarker sub‐study participation among other factors. Baseline standardized uptake value ratio (SUVR) was measured in composite brain regions of interest (ROIs) corresponding to Braak I‐II, Braak III‐IV, and Braak V‐VI regions using superior‐eroded cerebellum as the reference region. Tau extent (percentage of supra‐threshold voxels within an ROI relative to reference region), an exploratory measure of the spatial extent of 18F‐MK‐6240 binding, was also investigated.ResultThe baseline demographics of the Tau PET sub‐study population were consistent with the overall TANGO study population including clinical stage (MCI vs. mild AD), age, gender, APOE4, and clinical scores. At baseline, average SUVR (±SD) was 1.92±0.6 in Braak I‐II, 1.90±0.7 in Braak III‐IV and 1.75±0.8 in Braak V‐VI composite ROIs. The Braak composite SUVRs were positively associated with disease stage (i.e. higher SUVR with increasing disease severity). Exploratory analyses of extent were supportive of the SUVR results.ConclusionAt study baseline, tau SUVR was highest in Braak I‐II, followed by Braak III‐IV, then Braak V‐VI. Cross‐sectionally, higher tau PET SUVR was associated with increasing disease severity and worse clinical scores, as expected. The TANGO Tau PET sub‐study will aid our understanding of gosuranemab’s effect on tau pathology and further inform on the value of tau PET in clinical trials.

Ziel/Aim Progressive supranuclear palsy (PSP) is a 4-repeat (4R) tauopathy and region-specific tau deposits establish the neuropathological diagnosis of “definite PSP” post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers to validate the specific presence of the target before therapy initiation. The novel second generation tau-PET ligand 18F-PI2620 proved absent off-target binding to monoamine oxidases and high affinity to 3/4R tau in Alzheimer’s disease (AD). The aim of this multicenter-evaluation was to investigate 18F-PI2620 in patients with suspected 4R tau pathology in clinically diagnosed PSP.

The Bayesian penalized likelihood (BPL) reconstruction algorithm, Q.Clear, can achieve a higher signal-to-noise ratio on images and more accurate quantitation than ordered subset-expectation maximization (OSEM). The reconstruction parameter (β) in BPL requires optimization according to the radiopharmaceutical tracer. The present study aimed to define the optimal β value in BPL required to diagnose Alzheimer disease from brain positron emission tomography (PET) images acquired using 18 F-fluoro-2-deoxy-D-glucose ([18 F]FDG) and 11 C-labeled Pittsburg compound B ([11 C]PiB). Images generated from Hoffman 3D brain and cylindrical phantoms were acquired using a Discovery PET/computed tomography (CT) 710 and reconstructed using OSEM+time-of-flight (TOF) under clinical conditions and BPL+TOF (β=20-1000). Contrast was calculated from images generated by the Hoffman 3D brain phantom, and noise and uniformity were calculated from those generated by the cylindrical phantom. Five cognitively healthy controls and five patients with Alzheimer disease were assessed using [18 F]FDG and [11 C]PiB PET to validate the findings from the phantom study. The β values were restricted by the findings of the phantom study, then one certified nuclear medicine physician and two certified nuclear medicine technologists visually determined optimal β values by scoring the quality parameters of image contrast, image noise, cerebellar stability, and overall image quality of PET images from 1 (poor) to 5 (excellent). The contrast in BPL satisfied the Japanese Society of Nuclear Medicine (JSNM) criterion of ≥55% and exceeded that of OSEM at ranges of β=20-450 and 20-600 for [18 F]FDG and [11 C]PiB, respectively. The image noise in BPL satisfied the JSNM criterion of ≤15% and was below that in OSEM when β=150-1000 and 400-1000 for [18 F]FDG and [11 C]PiB, respectively. The phantom study restricted the ranges of β values to 100-300 and 300-500 for [18 F]FDG and [11 C]PiB, respectively. The BPL scores for gray-white matter contrast and image noise, exceeded those of OSEM in [18 F]FDG and [11 C]PiB images regardless of β values. Visual evaluation confirmed that the optimal β values were 200 and 450 for [18 F]FDG and [11 C]PiB, respectively. The BPL achieved better image contrast and less image noise than OSEM, while maintaining quantitative standardized uptake value ratios (SUVR) due to full convergence, more rigorous noise control, and edge preservation. The optimal β values for [18 F]FDG and [11 C]PiB brain PET were apparently 200 and 450, respectively. The present study provides useful information about how to determine optimal β values in BPL for brain PET imaging.

Subject motion in positron emission tomography (PET) studies leads to image blurring and artifacts; simultaneously acquired magnetic resonance imaging (MRI) data provides a means for motion correction (MC) in integrated PET/MRI scanners. To assess the effect of realistic head motion and MR-based MC on static [18 F]-fluorodeoxyglucose (FDG) PET images in dementia patients. Observational study. Thirty dementia subjects were recruited. 3T hybrid PET/MR scanner where EPI-based and T1 -weighted sequences were acquired simultaneously with the PET data. Head motion parameters estimated from high temporal resolution MR volumes were used for PET MC. The MR-based MC method was compared to PET frame-based MC methods in which motion parameters were estimated by coregistering 5-minute frames before and after accounting for the attenuation-emission mismatch. The relative changes in standardized uptake value ratios (SUVRs) between the PET volumes processed with the various MC methods, without MC, and the PET volumes with simulated motion were compared in relevant brain regions. The absolute value of the regional SUVR relative change was assessed with pairwise paired t-tests testing at the P = 0.05 level, comparing the values obtained through different MR-based MC processing methods as well as across different motion groups. The intraregion voxelwise variability of regional SUVRs obtained through different MR-based MC processing methods was also assessed with pairwise paired t-tests testing at the P = 0.05 level. MC had a greater impact on PET data quantification in subjects with larger amplitude motion (higher than 18% in the medial orbitofrontal cortex) and greater changes were generally observed for the MR-based MC method compared to the frame-based methods. Furthermore, a mean relative change of ∼4% was observed after MC even at the group level, suggesting the importance of routinely applying this correction. The intraregion voxelwise variability of regional SUVRs was also decreased using MR-based MC. All comparisons were significant at the P = 0.05 level. Incorporating temporally correlated MR data to account for intraframe motion has a positive impact on the FDG PET image quality and data quantification in dementia patients. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1288-1296.

Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

BackgroundWhite matter hyperintensity volume (WMHV) is a presumed marker of cerebrovascular disease associated with ageing, Alzheimer’s disease (AD) and vascular dementia. Higher baseline WMHV is associated with increased brain atrophy rate, with disproportionate effects in the hippocampus – a region affected early in AD. Understanding the relationships between longitudinal change in WMHV and hippocampal atrophy, while accounting for AD and cardiovascular risk factors, will increase our understanding of the multifactorial disease processes occurring during the early stages of AD.MethodRate of change in WMHV was calculated using Bayesian Model Selection (BaMoS) and total hippocampal atrophy rate was calculated using the Boundary Shift Integral (BSI), measured concurrently between two time‐points. Participants with major neurological disorders were excluded. Linear regression was used to test whether rates of WMHV change predicted rates of hippocampal atrophy while adjusting for total intracranial volume (TIV), sex and age. Further models adjusted for baseline PET amyloid‐β (Aβ) standard uptake value ratio (SUVR), ApoE‐e4 carrier status, and Framingham heart study cardiovascular risk (FHS‐CVS) aged 69, and tested for interactions with rate of WMHV change.Result308 individuals with high‐resolution isotropic MRI data at two time‐points were analysed in this study (Table 1). For every 1ml/year increase in WMHV there was an associated 0.013ml/year decrease in total hippocampal volume (Table 2, Model 1). This association remained when adjusting for Aβ SUVR (Table 2, Model 2), ApoE‐e4 status (Table 2, Model 3), and FHS‐CVS (Table 2, Model 4). A separate semi‐partial correlation analysis showed 4.6% of variance in rate of hippocampal atrophy was uniquely explained by rate of WMHV change when accounting for TIV, sex and age. There were no significant interactions between rate of WMHV change and Aβ, ApoE‐e4 or FHS‐CVS in relation to hippocampal atrophy rate.ConclusionIncreases in WMHV were significantly associated with progressive hippocampal atrophy accounting for head size, age and sex. These associations were not materially changed when adjusting for amyloid deposition, ApoE‐e4 or cardiovascular risk factors. These results suggest systemic processes that contribute to WMH development also contribute to hippocampal atrophy. Further work is required to determine the processes that drive this relationship.

Background Alzheimer disease (AD) progression can be monitored by tracking intensity changes in PET standardized uptake value (SUV) ratios of amyloid, tau, and neurodegeneration. The spatial extent ("fill state") of these three hallmark pathologic abnormalities may serve as critical pathophysiologic information, pending further investigation. Purpose To examine the clinical utility and increase the accessibility of PET-derived fill states. Materials and Methods This secondary analysis of two prospective studies used data from two independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Tau Propagation over Time study (T-POT). Each cohort comprised amyloid-negative cognitively normal individuals (controls) and patients with subjective cognitive decline, mild cognitive impairment, or probable-AD dementia. Fill states of amyloid, tau, and neurodegeneration were computed as the percentages of significantly abnormal voxels relative to controls across PET scans. Fill states and SUV ratios were compared across stages (Kruskal-Wallis H test, area under the receiver operating characteristic curve analysis) and tested for association with the severity of cognitive impairment (Spearman correlation, multivariate regression analysis). Additionally, a convolutional neural network (CNN) was developed to estimate fill states from patients' PET scans without requiring controls. Results The ADNI cohort included 324 individuals (mean age, 72 years ± 6.8 [SD]; 173 [53%] female), and the T-POT cohort comprised 99 individuals (mean age, 66 years ± 8.7; 63 [64%] female). Higher fill states were associated with higher stages of cognitive impairment (P < .001), and tau and neurodegeneration fill states showed higher diagnostic performance for cognitive impairment compared with SUV ratio (P < .05) across cohorts. Similarly, all fill states were negatively correlated with cognitive performance (P < .001) and uniquely characterized the degree of cognitive impairment even after adjustment for SUV ratio (P < .05). The CNN estimated amyloid and tau accurately, but not neurodegeneration fill states. Conclusion Fill states provided reliable markers of AD progression, potentially improving early detection, staging, and monitoring of AD in clinical practice and trials beyond SUV ratio. Clinical trial registration no. NCT00106899 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Yun and Kim in this issue.

In the management of brainstem lesions, the place of stereotactic biopsy sampling remains debatable. The authors compared the results of magnetic resonance (MR) imaging, positron emission tomography (PET) scanning, and histological studies obtained in 30 patients who underwent MR imaging- and PET-guided stereotactic biopsy procedures for a brainstem mass lesion. Between July 1991 and December 1998, 30 patients harboring brainstem mass lesions underwent a stereotactic procedure in which combined MR imaging and PET scanning guidance were used. Positron emission tomography scanning was performed using [18F]fluorodeoxyglucose in 16 patients, methionine in two patients, and both tracers in 12 patients. Definite diagnosis was established on histological examination of the biopsy samples. Interpretation of MR imaging findings only or PET findings only was in agreement with the histological diagnosis in 63% and 73% of cases, respectively. Magnetic resonance imaging and PET findings were concordant in 19 of the 30 cases; in those cases, imaging data correlated with histological findings in 79%. Treatment based on information derived from MR imaging was concordant with therapy based on histological findings in only 17 patients (57%). Combining MR imaging and PET scanning data, the concordance between the neuroimaging-based treatment and treatments based on histological findings increased to 19 patients (63%). In seven patients who underwent biopsy procedures with one PET-defined and one MR imaging-defined trajectory, at histological examination the PET-guided samples were more representative of the tumor's nature and grade than the MR imaging-guided samples in four cases (57%). In 18 patients PET scanning was used to define a biopsy target and provided a diagnostic yield in 100% of the cases. Although the use of combined PET and MR imaging improves radiological interpretation of a mass lesion in the brainstem, it does not accurately replace histological diagnosis that is provided by a stereotactically obtained biopsy sample. Combining information provided by MR imaging and PET scanning in stereotactic conditions improves the accuracy of targeting and the diagnostic yield of the biopsy sample; an MR imaging- and PET-guided stereotactic biopsy procedure is a safe and efficient modality for the management of mass lesions of the brainstem.

BackgroundTau tangle deposition is associated with Alzheimer disease (AD) clinical symptomology and cognitive decline. Such deposition can be measured in vivo using positron emission tomography (PET). Off‐target signal from extra‐cerebral sources, such as skull or meninges, may bias quantification but the impact is currently unknown. Here, we investigate off‐target sources in individuals with crossover 18F‐AV‐1451 and 18F‐MK‐6240 tau PET scans within the HEAD study.MethodT1‐weighted magnetic resonance imaging (MRI), Pittsburgh Compound B (PiB) amyloid PET, and tau PET were acquired for 42 participants. Tau PET scans were quantified using body‐weighted standardized uptake values (SUV) and SUV ratios (SUVRs) with cerebellar grey as the reference region. To isolate skull bone, CT scans from each participant were aligned to their own T1 image and threshold using a Hounsfield units cutoff derived from applying Gaussian mixture modeling on the average of all CT images to identify a skull bone compartment. For meninges, MNI‐152 aligned 18F‐MK‐6240 SUVR images were averaged and thresholded to identify voxels that potentially were meninges. This template was then transformed back into participant space and masked using the skull bone image and a brain mask to isolate those voxels that were neither bone nor brain but fell in‐between, producing a subject‐specific meningeal mask (Figure 1). Group average SUV images were created between amyloid negative and positive individuals.ResultAverage age of participants was 66 (21‐88) years. 25 were biologically female and 15 were amyloid positive. Group average SUV images show extra‐cerebral off‐target signal was more pronounced in 18F‐MK‐6240 for both amyloid negative and positive individuals compared to 18F‐AV‐1451 (Figure 2). The extra‐cerebral 18F‐MK‐6240 signal appeared across the entire cortical surface and posterior cerebellum, potentially impacting a cerebellar reference for tau PET SUVR quantification.ConclusionWhile off‐target extra‐cerebral signal appears in both tau PET tracers, it was more pronounced and wide‐spread in 18F‐MK‐6240. Subject‐specific skull and meningeal masks can parse this signal to aid in cause determination. Additional work is needed to explore factors contributing to this signal, such as demographic, health, and genetic.

Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease. To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET). Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia. We compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning. Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment. Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.