BACKGROUND:Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection. METHODS:We conducted a prospective, multicentre, non-randomised, within-participant comparison of [18F]flortaucipir (Tauvid), currently used in clinical settings in the USA and Europe, and [18F]MK6240, an investigational tau PET tracer. Participants were recruited from eight north American sites and underwent tau PET, amyloid-β (Aβ) PET, and detailed cognitive assessments. Tau PET with both agents was acquired within a 45-day window. Coprimary outcomes were the discriminative accuracy for Alzheimer's disease-related cognitive impairment and the frequency of tau positivity in early medial temporal lobe (MTL) and late neocortical regions. The study is registered with ClinicalTrials.gov, NCT05361382. FINDINGS:Between March 2, 2022, and Aug 27, 2025, 775 individuals were enrolled, with 682 completing all procedures (373 [55%] female, 309 [45%] male; 38 [6%] aged 19-27 years, 214 [31%] aged 50-65 years, and 430 [63%] aged 65-89 years). 32 (5%) participants identified as Hispanic or Latino. 637 (93%) identified as White, 24 (4%) as Black or African American, 16 (2%) as Asian, and five (1%) as other. In addition, 49 (7%) individuals were identified as being from a rural area. [18F]MK6240 showed greater accuracy than [18F]flortaucipir in distinguishing Alzheimer's disease from non-Alzheimer's disease impairment (area under the curve 0·93, 95% CI 0·89-0·95 vs 0·86, 0·75-0·91; p<0·0001). Among the older adults, tau positivity status was concordant in 560 (87%) for MTL and 603 (94%) for neocortical regions. In cognitively unimpaired participants, [18F]MK6240 identified twice as many MTL-positive cases as [18F]flortaucipir (n=54 [15%] vs n=23 [6%]). Prevalence ratio in Aβ-positive was 2·43 (95% CI 1·50-3·94; p=0·0003), identifying 23 additional cases per 100. Among discordant cases, 75 (89%) were [18F]MK6240-positive only and had higher Aβ burden (p<0·0001), APOEε4 frequency (p<0·0001), and cognitive impairment (p=0·0043) than those negative on both tracers. Neocortical tau positivity was more frequent with [18F]MK6240 than with [18F]flortaucipir in cognitively impaired individuals (80 [28%] vs 46 [16%]). Prevalence ratio in Aβ-positive was 1·74 (95% CI 1·32-2·29; p<0·0001), identifying 15 additional mild cognitive impairment and 21 dementia cases per 100. INTERPRETATION:Tau PET tracer selection influences the frequency of detection of tau pathology across the ageing and Alzheimer's disease spectrum. Compared with [18F]flortaucipir, [18F]MK6240 identified more individuals with tau pathology in cognitively unimpaired and cognitively impaired individuals, with direct implications for patient stratification in clinical trials and more precise guidance for therapeutic decision-making. FUNDING:National Institute on Aging.

Abstract Introduction The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p< 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p< 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

INTRODUCTION:Centiloid (CL) scaling standardizes amyloid positron emission tomography (PET) quantification across tracers and platforms; however, variability across software implementations may affect diagnostic classification. This study evaluated inter-software variability and diagnostic performance across five platforms using identical 1 8F-florbetapir datasets. METHODS:Retrospectively, 192 patients undergoing 1 8F-florbetapir PET/computed tomography (CT) and magnetic resonance imaging (MRI) were analyzed. CL values were generated using four US Food and Drug Administration (FDA) -cleared platforms and an in-house Centiloid standard pipeline. Agreement was assessed using intraclass correlation coefficient, with bias and limits of agreement evaluated by linear modeling and Bland-Altman analysis. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and classification against visual interpretation. RESULTS:Agreement was excellent (intraclass correlation coefficient [ICC] 0.969; 95%CI 0.961-0.975). Some platforms produced systematically higher CL values versus others slightly lower. LoA reached ± 30 CL. Diagnostic accuracy was high (area under the curve [AUC]: 0.949-0.975), with sensitivity 0.923-0.968 and specificity 0.667-0.806. DISCUSSION:Despite excellent agreement, systematic differences persist and may affect classification near thresholds, supporting consistent use of a single processing pipeline.

Individuals with both Alzheimer’s Disease (AD) and cerebrospinal fluid (CSF) dynamics disorders, such as idiopathic normal-pressure hydrocephalus (iNPH), exhibit reduced CSF Aβ42 levels, complicating the interpretation of AD biomarkers. However, the influence of CSF dynamics on blood-based AD biomarkers remains unclear. This study investigated whether immunoprecipitation mass spectrometry (IP-MS)-based AD plasma biomarkers were associated with disproportionately enlarged subarachnoid space hydrocephalus (DESH) on MRI. This retrospective, cross-sectional study included 509 participants from the Mayo Clinic Study of Aging who underwent MRI, [¹¹C] Pittsburgh compound B (Aβ) PET imaging, and plasma assessments of phosphorylated tau 217 (p-Tau 217), Aβ40, and Aβ42. Age-adjusted logistic regression analyses were conducted to evaluate whether abnormal levels of p-Tau 217,

Background Tau PET quantification typically requires structural MRI for reference-region definition, normalisation, and segmentation, which imposes a logistical and operational burden. In this study, we evaluated whether low-dose CT can serve as a reliable MRI alternative for tau PET quantification when MRI is unavailable. Methods In this multicentre, cross-sectional study comparing methods, we developed a PET–CT pipeline using low-dose CT as the sole anatomical reference for tau PET quantification. Participants were recruited from six sites in the multicentre Head-to-head Harmonisation of tau PET tracers (HEAD) study (NCT05361382). The cohort comprised cognitively unimpaired young adults (<28 years), cognitively unimpaired middle-aged adults (50–65 years), cognitively unimpaired older adults (>65 years), and participants with mild cognitive impairment or dementia. Participants underwent [18F]MK6240 and [18F]flortaucipir PET–CT, T1-weighted MRI, and amyloid PET. Standardised uptake value ratios were calculated for three Alzheimer’s disease-relevant composite regions and 34 individual brain regions using a template-based cerebellar reference and compared with PET–MR pipelines using template-based or FreeSurfer subject-space segmentation. Agreement was assessed using linear regression, intraclass correlation coefficients, Bland–Altman analysis, equivalence testing (two one-sided tests), and Cohen’s kappa (κ) for binary positivity concordance. Findings 387 participants were included, with recruitment spanning from Nov 11, 2022, to July 7, 2025 (205 [53%] women, 182 [47%] men; six [2%] aged 19–25 years, 130 [34%] aged 50–65 years, and 251 [65%] aged 66–89 years). CT-derived standardised uptake value ratios showed near-perfect linear correspondence with the template-based PET–MR pipeline for MK6240 (R2=0·959–0·975) and flortaucipir (0·925–0·964), with high absolute agreement (intraclass correlation coefficient 0·976–0·985 for MK6240 and 0·955–0·978 for flortaucipir). Against the FreeSurfer subject-space pipeline, correspondence remained strong for MK6240 (R2=0·952–0·971) and flortaucipir (0·909–0·949). Mean R2 across 34 brain regions was 0·917 (SD 0·049) for MK6240 and 0·874 (0·057) for flortaucipir. Tau-positivity concordance was high (92–97%; κ 0·802–0·895; all p<0·001), with discordant cases near the classification threshold. Associations with amyloid burden and memory were preserved across pipelines (Steiger’s test, all p>0·05). Equivalence was formally confirmed by two one-sided tests (all p<0·001). Interpretation CT-only processing enables robust tau PET quantification, comparable to standard MRI-based pipelines, including computationally intensive FreeSurfer-based approaches. This method was validated across different radiotracers and represents a reliable alternative when MRI is unavailable or contraindicated. Because low-dose CT is routinely acquired during PET–CT sessions, this approach enables quantification of legacy datasets without MRI, broadens participant inclusion in clinical trials, and can reduce imaging costs in settings where MRI is not clinically indicated. Funding National Institute on Aging.

Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its aetiology, clinical features and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, MN) over a 28-year period (January 1995 to December 2022). Clinical, neuropathological and neuroimaging data were analysed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited α-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer's disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n = 140), with dementia with Lewy bodies (DLB) being predominant (58%, n = 118), followed by mixed aetiologies ('two-hits') (18%, n = 36) and AD (10%, n = 21). Psychotic disorders accounted for 9% (n = 18) of cases. No case was attributed to a single stroke, although 9% (n = 19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g. visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n = 112). Capgras syndrome worsened in the evening or at night (87%, n = 45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n = 12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features-the number and type of targeted individuals-can help differentiate between neurodegenerative and psychiatric aetiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe) and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.

TPS6093 Background: Since patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th ed) have a 20-30% rate of occult nodal metastases despite clinical and radiographic assessment, standard of care treatment includes elective neck dissection (END). Many patients have comprehensive surgical management of the regional cervical nodal basin even though the majority of those necks (70-80%) will not contain disease. Assessment of draining first echelon lymph nodes by sentinel lymph node (SLN) biopsy (Bx), a less invasive surgical procedure, may provide an alternative to END, while potentially reducing morbidity and cost. A decisive clinical trial comparing SLN Bx versus END can focus the HNC clinical and research community and resources on establishing the standard of care for management of the neck in early-stage OCC. Methods: In order to address the efficacy of SLN Bx in this population, we recently activated an international multi-institutional phase II/III prospective trial randomizing patients to two surgical arms: SLN Bx and END. PET/CT is an integral imaging biomarker in this trial. A node-negative PET/CT study with central read is required before randomization. Patients with a positive PET/CT central result will remain in a registry to compare imaging findings with final neck pathology. Given the current evidence available regarding morbidity for SLN Bx versus END, the phase II will determine if patient-reported neck and shoulder function and related QOL at 6 months after surgery using the Neck Dissection Impairment Index (NDII) shows a signal of superiority of SLN Bx compared to END. A total of 228 randomized patients with negative PET/CT for potential evaluation of shoulder-related morbidity with difference in 6-month NDII scores (minimum important difference ³7.5; one-sided a = 0.10; 90% power) will serve as the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided alpha 0.05; 80% power, and an interim look for efficacy at 67% of the events based on an O’Brien-Fleming boundary). The NDII at 6 months after surgery is a hierarchical co-primary endpoint for the phase III. Target accrual of phase III is 618 PET/CT negative patients, including those randomized in phase II (297 DFS events required for the final analysis). In addition to radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course and SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END outcomes. As of 02/15/21, 7 patients have been screened and 6 of the planned 228 randomized patients in phase II have been enrolled. Clinical trial information: NCT04333537.

Abstract Introduction Patients with Parkinson’s disease commonly underreport sleep symptoms, but the extent to which such mismatch may be present in people with isolated RBD (iRBD) is unknown. We evaluated how the patient–bedpartner (PT–BP) mismatch in night-time and daytime sleep complaints relates to cognition, apathy, dopaminergic degeneration, and cortical structure in iRBD. Methods We retrospectively analyzed 425 iRBD participants (2018–2025) from the North American Prodromal Synucleinopathy (NAPS) Consortium with clinicodemographic data, dopamine transporter (DAT) imaging, and magnetic resonance imaging. Using Scales for Outcomes in Parkinson’s Disease (SCOPA)-Sleep, PT–BP mismatch was classified into overestimator (PT>BP), concordant (PT=BP), and underestimator (PT< BP) groups, separately for complaints during night and day. Outcomes included cognition (CDR-Sum of Boxes [CDR-SB], CDR-global, and individual subdomain tests), pareidolia, apathy, subregional DAT uptake, and cortical thickness. Group differences were tested with analysis of covariance adjusting for age, sex, disease duration, education, clinician-rated OSA treatment inadequacy, and the corresponding patient-reported SCOPA-Sleep domain (night or day), and estimated total intracranial volume for cortical thickness; pairwise tests used Bonferroni correction. Results The PT–BP mismatch was common (night – overestimator 127/425, 29.9% and underestimator 116/425, 27.3%; day – overestimator 77/425, 18.1% and underestimator 134/425, 31.5%). For night-time mismatch, underestimators showed lower CDR-SB and lower CDR-global than overestimators. In addition, underestimators exhibited more illusory responses, fewer correct noise rejections, and fewer total correct responses than overestimator and concordant groups. For daytime mismatch, CDR-SB was lower in underestimators versus overestimators; CDR-global was lower in underestimators and concordant participants versus overestimators. No significant associations were found for apathy. Subregional DAT uptake did not differ by mismatch group. Cortical thickness analyses revealed thinner right transverse gyrus in underestimator and concordant groups compared to the overestimator group and thinner left superior temporal gyrus in underestimator group compared to overestimator group, for night-time mismatch only. Conclusion The PT–BP subjective sleep mismatch can be used as a clinical marker associated with overall cognitive decline and cortical thinning in auditory and language processing areas, which may underlie impairment in perceptual interpretation and hallucination proneness. Further research is warranted to seek longitudinal change and phenoconversion in mismatch groups. Support (if any) #U19-AG071754 (NAPS Consortium)

A workgroup assembled by the Alzheimer's Association recently described a conceptual framework for Alzheimer's disease biological staging based on amyloid and tau PET imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer's disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer's Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer's Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer's disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer's disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer's Disease Neuroimaging Initiative cohort. This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer's disease into four biological stages with distinct characteristics.

BackgroundTAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent.ObjectiveThis study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo.MethodsPenalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda.ResultsThe model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology.ConclusionsThis study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Epilepsy, a prevalent neurological disorder worldwide, requires precise identification of the epileptogenic zone (EZ) to achieve optimal therapeutic outcomes, particularly in patients with drug-resistant epilepsy. Advanced neuroimaging plays a pivotal role in the presurgical evaluation of these patients. While [18F]fluorodeoxyglucose (FDG) remains the most widely utilized PET radiotracer in clinical practice, non-FDG radiotracers offer complementary molecular and neurochemical insights that extend beyond glucose metabolism. By targeting specific receptors, transporters, synaptic density, and neuroinflammatory processes, these tracers may improve the localization and biological characterization of the EZ. Although non-FDG PET radiotracers are still used predominantly in the research setting, ongoing advances in radiotracer development could further increase their clinical applicability in the evaluation of epilepsy. This review provides a comprehensive overview of currently available non-FDG PET radiotracers and summarizes their pathophysiological significance and promising clinical applications in epilepsy.

INTRODUCTION:Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS:Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS:Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death (n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION:Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Rapid eye movement sleep behavior disorder (RBD), a prodromal synucleinopathy that precedes Parkinson’s disease and related dementias, can present with subtle cognitive difficulties. However, limited data on longitudinal cognitive change in individuals with RBD has been presented. The present analysis aimed to quantify cognitive change across approximately one year in a cohort of individuals with polysomnogram-confirmed RBD (n=60 from the North American Prodromal Synucleinopathy Consortium), using previously validated standardized regression-based change scores developed in cognitively unimpaired participants from the National Alzheimer's Coordinating Center. In the entire sample, the mean change scores across the 13 cognitive scores ranged from -.37 to .04 compared to demographically matched peers. One-sample two-tailed t-tests revealed a significant decline on 1 of the 13 cognitive scores, category fluency for vegetables (p=.01), with small to medium effect size (d=.34). Although not statistically significant, subtle declines were also present on measures of attention (Number Backward, p= .06, d=.21), memory (Craft Story Delayed Recall, p=.18, d=.17), processing speed (Trail Making A, p=.22, d=.16), and visuospatial skills (Benson Copy, p=.23, d=.16). Overall, during this prodromal period, individuals with RBD appear to remain largely cognitively stable over approximately one year. Nonetheless, continued tracking of these individuals may provide important prognostic information and/or endophenotyping of patients. These results also have potential implications for clinical management and the design of clinical trials in RBD.

Tau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake. In this study, we tested the impact of various methods to determine tau positivity using two different tau PET tracers in individuals scanned head-to-head. We studied 147 individuals from Head-to-Head Harmonization of Tau Tracers in Alzheimer's Disease (HEAD) study with tau tangle PET scans with [ 18 F]Flortaucipir and [ 18 F]MK-6240, and amyloid-β (Aβ) PET. Tau deposition was measured with the standardized uptake value ratio (SUVR) of each agent in the Medial Temporal Lobe (MTL) and the Entorhinal Cortex (EC). To determine Tau positivity three different methods were used: >2.5 standard deviations (SD) than the mean of the young, >1.5 SD mean of the cognitively unimpaired (CU) and >1.5 SD mean of CUAβ-. Demographic characteristics of the study population are reported in Table 1. Using the cutoff >2.5 SD mean of young, [ 18 F]Flortaucipir was positive in 35 (23.8%) and 69 (46.9%) individuals in the EC and MTL, respectively. [ 18 F]MK-6240 was positive in 49 (33.3%) and 58 (39.5%) individuals in EC and in MTL. Using >1.5 SD mean of CUAβ-, [ 18 F]Flortaucipir was positive in 38 (25.9%) and 45 (30.6%) individuals in EC and MTL, while [ 18 F]MK-6240 was positive in 51 (34.7%) and 50 (34.0%) in EC and in MTL (Figure 1). Our findings indicate variations in tau positivity when employing different methods based on either the young or CUAβ-. [ 18 F]Flortaucipir exhibited a higher rate of positive results when the method based on young individuals was applied in the MTL. Conversely, [ 18 F]MK-6240 showed more consistent and generally higher positivity when other methods were used for cutoff determination and/or in the EC region. Further research with a larger sample size is required to gain a better understanding of the optimal cutoff determination methods for these tracers.

The HEAD study aims to collect a large dataset of multiple tau-PET tracers to provide robust anchor values for tau-PET harmonization. Here, we tested the hypothesis that anchoring two tau tracer uptake values using head-to-head measurements has the potential to generate an accurate universal tau-PET scale, named Uniτ(tau). We assessed 200 individuals across the aging and AD spectrum (Training: HEAD data freeze 2.0, n=185; Testing: UPitt dataset (Gogola et al.), n=15) with [ 18 F]Flortaucipir and [ 18 F]MK-6240 tau-PET. SUVRs were processed to a common 8mm FWHM, with inferior cerebellar gray matter as the reference region (Pascoal et al.). Uniτ explored two anchoring/harmonization methods. First, we examined within-tracer anchoring by creating anchor values based on the mean SUVR of Youngs (<25 years) and 95th percentile voxels from cognitively impaired individuals. Second, we explored within- plus between-tracer anchoring, employing linear (e.g., piecewise) and non-linear regressions. To address the inherent problem of discontinuity of piecewise transformations, we implemented two smoothing methods at the inflection point between equations, transforming them into a continuous function. Uniτ scale anchoring within-tracer resulted in similar estimates for high values, but less accurate in the lower range (Figure 1,2). Anchoring within- plus between-tracer improved estimate consistency, with the piecewise transformation generating the best results. The piecewise smoothing equation yielded estimates comparable to those obtained from the piecewise method without smoothing. This allowed for the use of a single formula. In addition, this leads to more robust results when the goal is to study longitudinal changes in the scale (data not shown). UPitt testing dataset showed similar results to the training set (Figure 3). Our preliminary findings suggest that anchoring tau-PET values both within and between tracers has the potential to harmonize tau-PET tracers, while preserving their characteristics. Currently, piecewise smoothing is the preferred method for Uniτ, but we are continuously fine-tuning scale parameters as we acquire more data. The final scale parameters will be determined based on extensive training and testing data from multiple tracers. This cautious methodology holds the promise of delivering reliable, robust, and reproducible results, ensuring safe usage of the scale in clinical trials, and potentially paving the way for future use in clinical practice.