Pascual, Belen

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 Background Tau‐PET tracers are essential for visualizing pathology in Alzheimer’s (AD). High detectability to tau is crucial for early detection and monitoring of tau deposition. This study compares the noise to dynamic range ratio (NRR) of [ 18 F]FTP, [ 18 F]MK6240, [ 18 F]PI2620, and [ 18 F]RO948, cross‐sectionally and longitudinally. Methods 460 individuals from the HEAD study (23 cognitively unimpaired (CU) young, 249 CU old and 188 cognitively impaired) underwent [ 18 F]FTP and [ 18 F]MK6240 tau‐PET scans; 94 additionally received [ 18 F]PI2620 and [ 18 F]RO948. A subset of 28 individuals (15 CU and 13 CI) underwent [ 18 F]FTP and [ 18 F]MK6240 follow‐up scans (1.5 ± 0.1 years later). Annual change was measured as [(followup‐baseline)/time between scans]. Noise was calculated as the standard deviation (SD) of CU Aβ‐ participants aged ≤65 (SD CUAβ‐≤65 ). The dynamic range was calculated as the SD across all subjects (SD range ). A lower the NRR (=SD CUAβ‐≤65 /SD range ) indicates more detectability. Analyses were performed at both region‐of‐interest and voxel‐wise levels. Results Across the whole cohort, [ 18 F]MK6240 exhibited lower NRR than [ 18 F]FTP in all regions. Voxel‐wise, differences were most pronounced in the frontal medial temporal regions (Figure 1). Within the four‐tracers subset, [ 18 F]PI2620 and [ 18 F]FTP showed the highest NRR in Braak II, followed by [ 18 F]RO948 and [ 18 F]MK6240. In Braak IV‐VI, [ 18 F]MK6240 consistently demonstrated the lowest values, followed by [ 18 F]PI2620, [ 18 F]FTP and [ 18 F]RO948. Similarly, in metatemporal‐ROI and Braak III, [ 18 F]MK6240 remained the lowest, however followed by [ 18 F]FTP, [ 18 F]PI2620 and [ 18 F]RO948 (Figure 2). Lower [ 18 F]MK6240 NRR was due to larger SD range , while [ 18 F]FTP's lower values stemmed from smaller SD CUAβ‐≤65 . Conversely, high [ 18 F]PI2620 and [ 18 F]RO948 values are driven by larger SD CUAβ‐≤65 . Longitudinal analyses further confirmed that [ 18 F]MK6240 exhibited the lowest NRR across the entire brain, including AD‐related regions, with voxel‐wise differences mainly in the temporal and parietal lobes. Conclusion Tau‐PET tracers exhibit significant variability in detectability. [ 18 F]MK6240 consistently demonstrated lower NRR, implying better detectability across all regions, cross‐sectionally and longitudinally. Despite differences in NRR, [ 18 F]FTP, [ 18 F]RO948 and [ 18 F]PI2620 followed similar pattern. These results provide insights into the differential tracer detectability, helping guide their optimal use in detecting and tracking tau pathology. Ongoing follow‐up scans will further clarify longitudinal tracer detectability and its implications for tau progression in AD.

Abstract Background Tau‐PET tracers have been used to monitor the progression of Alzheimer’s disease (AD). However, different tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their findings. Leveraging the HEAD Study, the largest head‐to‐head study of tau‐PET tracers, we recently developed the Uniτ scale, which cross‐sectionally harmonizes Flortaucipir and MK6240 onto a universal tau‐PET measurement. Here, we provide a preliminary evaluation of the Uniτ scale’s longitudinal performance in HEAD and two independent cohorts. Methods We assessed 422 individuals across the AD spectrum with longitudinal tau‐PET from three cohorts: HEAD [13 cognitively unimpaired (CU), 9 cognitively impaired (CI) individuals, scanned head‐to‐head with Flortaucipir and MK6240], ADNI [74 CU, 208 CI, tracer: Flortaucipir], and TRIAD [72 CU, 46 CI, tracer: MK6240]. Standardized uptake ratios (SUVRs) were harmonized to Uniτ using the Uniτ Ecosystem ( unitau.app ). Braak I‐II and the Meta‐Temporal regions were used as regions of interest. Annual tau‐PET uptake change was calculated, and the effect size was defined as the mean annual change divided by its standard deviation. Results In HEAD, annual change in tau‐PET uptake in Braak I‐II across CU and CI was only detectable in MK6240 (Figure 1A). However, both tracers detected significant annual changes in the Meta‐Temporal ROI for CI (Figure 1B). In both ADNI (Flortaucipir) and TRIAD (MK6240), changes in tau‐PET uptake in Braak I‐II regions were not significant (Figures 2‐3A). However, across all cohorts, the Meta‐Temporal ROI consistently showed detectable annual tau‐PET increases—most pronounced among CI—leading to larger effect sizes than in Braak I‐II (Figures 1‐3B). The Uniτ harmonization did not fundamentally alter the pattern of the findings. However, in ADNI (Flortaucipir), Uniτ yielded a slightly higher effect size than SUVR in CU for both Braak I‐II and Meta‐Temporal regions. Conclusion In this large longitudinal sample, our findings confirm that Flortaucipir and MK6240 can detect tau PET changes over time likely associated with the progression of tau tangle pathology. While MK6240 appears to show greater progression in CU, both tracers progress similarly in CI. Our data also suggested that Uniτ harmonized tau PET measurements maintain the longitudinal characteristics of each tau PET tracer for use in clinical trials.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Aim Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may guide development of future therapies. Methods Participants ( n = 354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤1) or advanced (CDR® plus NACC FTLD ≥1). Baseline and annual follow‐up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory‐Questionnaire and Clinician Judgment of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. Results NPS were highly prevalent (≥90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression showed the least visit‐to‐visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit‐to‐visit in more than 50% of cases. Symptoms in the affective and disinhibited cluster were associated with the highest caregiver burden, while symptoms in the obsessive cluster were associated with the most functional impairment. Conclusion NPS in bvFTD are frequent and cluster into four discrete groups. The fluctuating nature of some NPS in bvFTD suggests that they may not be reliable markers of disease progression or stage.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

Abstract INTRODUCTION Psychotropic medication (PM) use in behavioral‐variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. METHODS We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART). RESULTS We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants. DISCUSSION Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated. Highlights We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.