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Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Abstract Background The Alzheimer's disease (AD) Braak staging is a key framework for classifying tau pathology progression in AD based on histopathological post‐mortem brain examinations. However, adapting it to PET imaging can be challenging due to differences in tracer uptake patterns and binding properties, which affect sensitivity, specificity, and regional staging. This study compares Braak staging across four tau PET tracers: Flortaucipir, MK6240, PI2620, and RO948. Methods We assessed 90 participants across the AD spectrum (46 CU, 31 MCI, 13 dementia; mean age 66.1 ± 7.8) using Aβ PET and four tau PET tracers: (Flortaucipir, MK6240, PI2620, and RO948). Braak positivity was defined based on Aβ− CU individuals (mean +2.5 SD, SUVR). To evaluate systematic bias and agreement between tracers, we computed pairwise differences at corresponding Braak stage estimates and applied the Bland‐Altman method to assess mean bias and limits of agreement. Additionally, Tau PET Braak region trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Results Braak stage trajectories as a function of Aβ differ depending on the tracer and the sequential order of abnormality is highly variable. For instance, while for MK6240, RO948 and PI2620, Braak I is the first region to became abnormal, for Flortaucipir the earliest region to became abnormal is Braak IV (Figure 1). This variable pattern of abnormality impacts in the concordance of Braak staging between tracers with the highest Braak staging agreement resulting in concordance levels of approximately 70%. The highest levels of agreement between tracers usually happen at Braak 0 or Braak IV‐V, with intermediate stages showing very low concordance (Figure 2). The Bland‐Altman analysis identified wide limits of agreement, suggesting high variability and high tracer‐specific differences (Figure 3). On the other hand, it also identified that mean differences between tracers were small, indicating minimal systematic bias. Conclusion These preliminary findings reveal discrepancies in Braak staging when comparing Flortaucipir, MK6240, PI2620 and RO948. These findings suggest that while the tracers provide comparable stages on average, they may not be fully interchangeable in individual cases.

Abstract Introduction Cervical arterial dissections (CeAD) can involve either single (sCeAD) or multiple (mCeAD) arteries. Whether the involvement of a single versus multiple arteries is associated with outcomes remains unclear. We aimed to study associations between the number of affected arteries and clinical, imaging and outcome parameters. Patients and methods Patients with CeAD from the STOP-CAD multicenter registry study were included. Clinical, imaging, treatment and outcome parameters were compared between patients with sCeAD and mCeAD. Regression analyses were performed to identify associations with multi-arteries involvement. Results Overall, 3858 STOP-CAD patients were included in this analysis and 443 (11.5%) had mCeAD. The presence of mCeAD was associated with age (adjusted odds ratio [aOR] 95% confidence intervals [95% CI] 0.99; (0.98–1.00)), female sex (aOR 1.5; 95% CI 1.17–1.91), recent upper respiratory infection (aOR 2.25; 95% CI 1.55–3.27), presence of connective tissue disease (aOR 3.11; 95% CI 2.32–4.17), severe arterial stenosis (aOR 1.95; 95% CI 1.95–2.58), intracranial extension (aOR 1.47; 95% CI 1.04–2.09), vertebral artery involvement (aOR 2.50; 95% CI 1.94–3.22) and presence of dissecting aneurysm (aOR 2.59; 95% CI 1.95–3.42). In adjusted analyses, mCeAD was not associated with clinical outcomes (ischemic stroke, mortality, and sICH; all p > 0.05). Conclusions mCeAD does not appear to increase risk of subsequent stroke as compared to sCAD despite baseline risk factors suggestive of vasculopathy. mCeAD patients who did develop a stroke presented with milder strokes and less often had vessel occlusions compared to those with sCeAD. The presence of mCeAD did not impact outcomes.

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Abstract Background Older adults with brain tau pathology but no evident amyloid‐beta (A) pathology can be referred to as primary age‐related tauopathy (PART). However, in vivo characterization of PART using biomarkers remains unclear, varying based on the method used to define tau pathology (e.g. different tau‐PET tracers). Here, we conducted a head‐to‐head characterization of PART using two different tau‐PET tracers. Method We studied 433 individuals from the HEAD cohort (244 CU, 138 MCI, and 51 with dementia). Participants underwent clinical assessments, MRI, A‐PET, both MK‐6240 and Flortaucipir scans, and a subset with plasma biomarkers ( n = 332). A‐PET positivity was defined as Centiloid>24. Tau‐positivity(T) was determined by MK‐6240 and Flortaucipir SUVR values exceeding the mean+2SD in at least one Braak region anchored in CU A‐ individuals followed by visual confirmation in A‐/T+ cases. Concordance across biomarkers was assessed among PART (A‐/T+), A‐/T‐ and A+/T+ groups. Plasma GFAP, p ‐tau217, NFL levels, and Centiloids were compared across A/T groups using linear regression. Result We found a total of 25 (5.8 %) cases classified as A‐/T+ defined by at least one tau tracer (74±6.3 years, 52% females, 17 CU, 3 MCI, 5 with dementia). Detection of A‐/T+ cases varied by tracer: MK‐6240( n = 20), Flortaucipir( n = 16) (Figure 1A). Among A‐/T+ individuals, MK‐6240 identified 13 CU, 4 MCI, and 3 dementia cases, while Flortaucipir identified 11 CU, 3 MCI, and 2 dementia cases(Figure 1B). Concordance between MK‐6240 and Flortaucipir in A‐/T+ cases was low ( n = 11, 44%)(Figure 1C). A‐/T+ individuals showed no significant biomarker differences from A‐/T‐ but had lower biomarker levels than A+/T+: Centiloids (MK‐6240: T=15.08, p <0.001; Flortaucipir: T=14.36, p <0.001), GFAP (MK‐6240: T=5.04, p < 0.01; Flortaucipir: T=2.92, p <0.001), p ‐tau217 (MK‐6240: T=7.77, p <0.001; Flortaucipir: T=6.34, p <0.001), except for NFL (MK‐6240: T=1.35, p = 0.18; Flortaucipir: T=1.14, p = 0.25)(Figure 2). Representative A and tau biomarker cases (Figure 3A), along with discordant cases classified as T+ by only one tracer (Figure 3B), are illustrated. Conclusion Our preliminary analysis revealed a higher prevalence of A‐/T+ cases with MK‐6240 than Flortaucipir, low concordance between tracers and consistently lower biomarker levels in A‐/T+ compared to A+/T+. Larger studies and longitudinal analyses are necessary to ascertain the pathological trajectories of A‐/T+ individuals with varying tau biomarker profiles.

Abstract Background Tau phosphorylation and aggregation are hallmark features of Alzheimer's disease pathology(AD). Previous studies have shown that plasma phosphorylated tau( p ‐tau) at threonine 217 can detect AD‐related tau tangle pathology. However, the head‐to‐head association between p ‐tau217 and different tau PET tracers remains unexplored. Here, we conducted a head‐to‐head comparison of the association between plasma p ‐tau217 and four distinct tau PET tracers[MK6240, Flortaucipir(FTP), PI2620, RO948]. Method We studied 338 individuals across the AD continuum from the HEAD study[190 cognitively unimpaired elderly(CU), 109 with mild cognitive impairment(MCI), and 39 with dementia] with available FTP, MK6240, and plasma p ‐tau217 measured by ALZpath assay. A subset of 64 individuals(28 CU, 25 MCI, and 11 dementia) also had PI2620 and RO948, and p ‐tau217 measured by Lumipulse. The strength of the association was determined using t‐value maps from regression models testing the association between each tau PET tracer and plasma p ‐tau217, and the extent was measured by the percentage of significant voxels(t‐value>3.2). R‐square metric was used to determine how much of the variance in tau PET tracer estimates was explained by plasma p ‐tau217 concentrations. Associations between p ‐tau217 with tau PET were evaluated using the Spearman test. Result We found that in CU, both the extent and magnitude of the association with plasma p ‐tau217 were higher for MK6240 compared to FTP (Figure 1A‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240 than in FTP (Figure 1E‐F). In CI, the extent and magnitude of the association were similar for MK6240 and FTP. Additionally, plasma p ‐tau217 explained a similar proportion of the variance in MK6240 and FTP. Using the subset of individuals who had all tau tracers, MK6240 showed a slightly higher extent of association with p ‐tau217, followed by FTP, PI2620, and RO948 (Figure 2A‐B). The magnitude of association was stronger for MK6240, followed by PI2620, RO948, and FTP (Figure 2C‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240, followed by FTP, RO948, and PI2620 (Figure 2E‐F). We compared the associations between different p ‐tau217 assays, and both assays presented similar associations with all tau PET tracers (Figure 3). Conclusion In summary, our results indicate that the four tau PET tracers exhibit robust associations with plasma p ‐tau217 in similar topographical regions.

Abstract Background The overlap index (OI), previously introduced by Lee et al. (2022), has proven to be a reliable method for detecting tau accumulation via tau‐PET imaging with flortaucipir ([ 18 F]AV‐1451). This technique identifies voxel‐wise increases in standardized uptake value ratio (SUVr) across serial scans. However, the relationship between tau‐PET measurements obtained with [ 18 F]MK‐6240 and [ 18 F]AV‐1451 using the OI remains unclear. This study aims to investigate the relationship between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET using the tau‐PET OI. Method The study included 27 participants from the HEAD project, all of whom underwent two serial tau‐PET scans (each [ 18 F]MK‐6240 and [ 18 F]AV‐1451) along with 3T T1‐weighted MRI, acquired within an average interval of 18 months. SUVr maps for each tau‐PET tracer were normalized to the cerebellar crus grey matter, and MR images were co‐registered to the MCALT T1 template. Tau‐PET images were spatially resampled to the template space, and OI was computed within a predefined META‐ROI using an intensity threshold of 1.3 and a cutoff of 0.5. Clusters containing fewer than 20 contiguous voxels were excluded from analysis. The META‐ROI SUVr was calculated as the average SUVr across the selected region's SUVr. Additionally, a visual comparison was performed to assess the spatial overlap of OI‐identified voxels between the two tau‐PET tracers. Result OI values within the META‐ROI exhibited a broad distribution between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET, particularly in cognitively unimpaired (CU) and younger individuals (Figure 1A). Unlike the OI distribution, the relationship between META‐ROI SUVr values of both tracers followed an exponential trend (Figure 1B). Visual inspection revealed that OI‐detected voxels in [ 18 F]MK‐6240 tau‐PET were frequently localized to the meninges, an established site of off‐target binding, which was not observed in [ 18 F]AV‐1451 tau‐PET (Figure 2). Conclusion The association between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET, as assessed using the OI, exhibited considerable variability in CU and younger participants. Additionally, the presence of overlapping voxels in the meninges in [ 18 F]MK‐6240 tau‐PET highlights the need to account for and potentially exclude off‐target binding effects in these populations. The influence of meningeal signal and other off‐target binding on the OI in the temporal META‐ROI needs to be further evaluated.

Abstract Background Tau accumulation in the brain is postulated to follow a hierarchical pattern, known as Braak staging, originally defined in postmortem brains. PET‐based Braak stages have since been proposed, however, tau PET tracers exhibit distinct binding characteristics that might influence the detectable trajectories of tau accumulation and its relationship with other biomarkers across the AD continuum. In a head‐to‐head study, we investigated the emergence of tau positivity in each Braak region, along with plasma p ‐tau217 and GFAP, as a function of Aβ PET deposition. Method We evaluated 352 individuals from the HEAD study (205 cognitively unimpaired and 147 cognitively impaired) with head‐to‐head Aβ PET, MK6240 and Flortaucipir tau PET, and plasma p ‐tau217 (ALZpath) and GFAP (Quanterix) measures. Tau PET Braak regions, plasma p ‐tau217 and GFAP trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Biomarkers were z‐scored anchored on young individuals ( n = 19, <28 years old). Positivity for plasma biomarkers and for each Braak region was determined when values surpassed 2.5 z‐score from the mean. Result Among the tested markers, plasma GFAP was the earliest to show abnormality as a function of Centiloid, occurring at 11 Centiloids. For MK6240, Braak I was the first regions to became positive (at 22 Centiloids), followed by Braak II (at 32 Centiloids), Braak IV (at 42 Centiloids), Braak III (at 52 Centiloids), Braak V (at 70 Centiloids) and Braak VI (at 123 Centiloid; Figure 1A). For Flortaucipir the first region to became positive was Braak IV (at 50 Centiloids), followed by Braak I and II (both at 56 Centiloids), Braak III (at 85 Centiloids) and Braak V (at 92 Centiloids). Braak VI region did not reach the threshold for positivity in our population (Figure 1B). Plasma p ‐tau217 reached the positivity threshold at 38 Centiloids. Conclusion MK6240 follows a Braak stage‐like pattern of abnormality as a function of Aβ burden, whereas for Flortaucipir, Braak IV is the first region to became abnormal. MK6240 becomes abnormal at lower Aβ burden levels compared to plasma p ‐tau217 and Flortaucipir but after plasma GFAP. Our findings suggest that MK6240 might detect tau pathology in earlier disease stages than Flortaucipir.