Positron Emission Tomography Biomarkers Research Articles

The dilemma and comprehensive assessment for a precise diagnosis of Alzheimer's disease

The clinical and neuroimaging findings of Alzheimer's disease (AD) are significantly heterogeneous. There are uncertaintie in the current widely available clinical and imaging diagnosis of AD. In the era of amyloid-targeted monoclonal antibody therapy, accurate diagnosis of Alzheimer's disease is urgently needed. Positron emission tomography (PET) and cerebrospinal fluid (CSF) examination can effectively reflect the β-amyloid and neurofibrillary tangles pathology in AD, thus effectively improving the accuracy of AD diagnosis. Understanding the value of various CSF and PET biomarkers in diagnosing/staging AD is a prerequisite for clinical application of biomarkers. The selection and interpretation of biomarkers should fully consider the clinical features and structural imaging of dementia patients, while paying attention to the degree of concordance between the clinical stages and the biological stages reflected by the biomarkers. Thus, biomarkers are expected to play more additional value in AD diagnosis and treatment.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

While immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression – a central feature of AD – remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Use of a Blood Biomarker Test Improves Economic Utility in the Evaluation of Older Patients Presenting with Cognitive Impairment.

More than 16 million Americans living with cognitive impairment warrant a diagnostic evaluation to determine the cause of this disorder. The recent availability of disease-modifying therapies for Alzheimer's disease (AD) is expected to significantly drive demand for such diagnostic testing. Accurate, accessible, and affordable methods are needed. Blood biomarkers (BBMs) offer advantages over usual care amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in these regards. This study used a budget impact model to assess the economic utility of the PrecivityAD® blood test, a clinically validated BBM test for the evaluation of brain amyloid, a pathological hallmark of AD. The model compared 2 scenarios: (1) baseline testing involving usual care practice, and (2) early use of a BBM test before usual care CSF and PET biomarker use. At a modest 40% adoption rate, the BBM test scenario had comparable sensitivity and specificity to the usual care scenario and showed net savings in the diagnostic work-up of $3.57 million or $0.30 per member per month in a 1 million member population, translating to over $1B when extrapolated to the US population as a whole and representing a 11.4% cost reduction. Savings were driven by reductions in the frequency and need for CSF and PET testing. Additionally, BBM testing was associated with a cost savings of $643 per AD case identified. Use of the PrecivityAD blood test in the clinical care pathway may prevent unnecessary testing, provide cost savings, and reduce the burden on both patients and health plans.

Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia.

Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals. Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aβ plasma-/PET- (NC=22, MCI=60), plasma+/PET- (NC=5, MCI=20), and plasma+/PET+ (AD dementia=21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aβ42/40 and p-tau181. FW imaging changes distinguish plasma Aβ42/40 positive and negative groups, independent of group differences in cognitive status, Aβ PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). Plasma Aβ42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aβ42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Blood-based biomarkers in Alzheimer's disease- moving towards a new era of diagnostics.

Alzheimer's disease (AD), a primary cause of dementia globally, is traditionally diagnosed via cerebrospinal fluid (CSF) measures and positron emission tomography (PET). The invasiveness, cost, and limited accessibility of these methods have led to exploring blood-based biomarkers as a promising alternative for AD diagnosis and monitoring. Recent advancements in sensitive immunoassays have identified potential blood-based biomarkers, such as Aβ42/Aβ40 ratios and phosphorylated tau (p-tau) species. This paper briefly evaluates the clinical utility and reliability of these biomarkers across various AD stages, highlighting challenges like refining plasma Aβ42/Aβ40 assays and enhancing the precision of p-tau, particularly p-tau181, p-tau217, and p-tau231. The discussion also covers other plasma biomarkers like neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and synaptic biomarkers, assessing their significance in AD diagnostics. The need for ongoing research and development of robust assays to match the performance of CSF and PET biomarkers is underscored. In summary, blood-based biomarkers are increasingly crucial in AD diagnosis, follow-up, prognostication, treatment response evaluation, and population screening, particularly in primary care settings. These developments are set to revolutionize AD diagnostics, offering earlier and more accessible detection and management options.

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts. This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity. This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

Resting-State Functional MRI and PET Imaging as Noninvasive Tools to Study (Ab)Normal Neurodevelopment in Humans and Rodents.

Neurodevelopmental disorders (NDDs) are a group of complex neurologic and psychiatric disorders. Functional and molecular imaging techniques, such as resting-state functional magnetic resonance imaging (rs-fMRI) and positron emission tomography (PET), can be used to measure network activity noninvasively and longitudinally during maturation in both humans and rodent models. Here, we review the current knowledge on rs-fMRI and PET biomarkers in the study of normal and abnormal neurodevelopment, including intellectual disability (ID; with/without epilepsy), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), in humans and rodent models from birth until adulthood, and evaluate the cross-species translational value of the imaging biomarkers. To date, only a few isolated studies have used rs-fMRI or PET to study (abnormal) neurodevelopment in rodents during infancy, the critical period of neurodevelopment. Further work to explore the feasibility of performing functional imaging studies in infant rodent models is essential, as rs-fMRI and PET imaging in transgenic rodent models of NDDs are powerful techniques for studying disease pathogenesis, developing noninvasive preclinical imaging biomarkers of neurodevelopmental dysfunction, and evaluating treatment-response in disease-specific models.

The role of biofluid markers in predicting near‐term cognitive impairment

AbstractBackgroundAlzheimer’s disease (AD) has been defined as a biological construct that can be determined using in vivo biomarkers. Recent studies confirmed the clinical value of the AT(N) framework when using Aβ and tau positron emission tomography (PET) scans in predicting progression from cognitively unimpaired to MCI. Our study aims to investigate if plasma biomarkers can yield similar predictive performance to PET biomarkers, and to also compare against cerebrospinal fluid (CSF) biomarkersMethodIndividuals from the PREVENT‐AD cohort were included in the study. Participants had Aβ and tau plasma measurements and at least one year of clinical follow‐up thereafter (n = 278). A subset of participants had CSF measurements (n = 102) and/or PET scans (n = 133) also with 1‐year clinical follow‐up. Participants were cognitively unimpaired at the time of all biomarker measurements. MCI diagnoses were made by clinical consensus among expert clinical and research staff blind to plasma, CSF, PET, MRI and APOE genotype. We established thresholds of plasma and CSF Aβ and tau positivity based on >80% specificity in identifying individuals with significant levels of Aβ‐PET (plasma Aβ42/40 = 0.057; plasma pTau181 = 7.53 pg/mL; CSF Aβ42 = 961.37; CSF pTau181 = 66.59 pg/mL). Aβ ([18F]NAV4694) and tau ([18F]AV1451)PET thresholds were defined by the mean plus 2 standard deviations from young participants (Aβ SUVR cut‐off = 1.17; tau SUVR cut‐off = 1.24).Result36.8% (7/19) of the A+T+ plasma group progressed to MCI, 50% (4/8) of the A+T+ CSF group progressed to MCI, and 46.6% (7/15) A+T+ PET group progressed to MCI (Fig. 1).We found differences in MCI progression status between the A+T+ group compared to the A‐T‐ and A+T‐ groups across all biomarkers’ measurements, with the A+T+ group always showing a higher rate of progression than the other two groups (post‐hoc chi‐square analyses; p<0.05).ConclusionAbnormal levels of Aβ and tau plasma biomarkers can help predict near‐ term progression to MCI. When plasma thresholds are derived based on PET data, however, plasma biomarkers have a slightly lower specificity than PET and CSF biomarkers, and both plasma and CSF biomarkers are less sensitive than PET biomarkers.

The role of biofluid markers in predicting near‐term cognitive impairment

AbstractBackgroundAlzheimer’s disease (AD) has been defined as a biological construct that can be determined using in vivo biomarkers. Recent studies confirmed the clinical value of the AT(N) framework when using Aß and tau positron emission tomography (PET) scans in predicting progression from cognitively unimpaired to MCI. Our study aims to investigate if plasma biomarkers can yield similar predictive performance to PET biomarkers, and to also compare against cerebrospinal fluid (CSF) biomarkersMethodIndividuals from the PREVENT‐AD cohort were included in the study. Participants had Aß and tau plasma measurements and at least one year of clinical follow‐up thereafter (n = 278). A subset of participants had CSF measurements (n = 102) and/or PET scans (n = 133) also with 1‐year clinical follow‐up. Participants were cognitively unimpaired at the time of all biomarker measurements. MCI diagnoses were made by clinical consensus among expert clinical and research staff blind to plasma, CSF, PET, MRI and APOE genotype. We established thresholds of plasma and CSF Aß and tau positivity based on >80% specificity in identifying individuals with significant levels of Aß‐PET (plasma Aß42/40 = 0.057; plasma pTau181 = 7.53 pg/mL; CSF Aß42 = 961.37; CSF pTau181 = 66.59 pg/mL). Aß ([18F]NAV4694) and tau ([18F]AV1451)PET thresholds were defined by the mean plus 2 standard deviations from young participants (Aß SUVR cut‐off = 1.17; tau SUVR cut‐off = 1.24).Result36.8% (7/19) of the A+T+ plasma group progressed to MCI, 50% (4/8) of the A+T+ CSF group progressed to MCI, and 46.6% (7/15) A+T+ PET group progressed to MCI (Fig. 1).We found differences in MCI progression status between the A+T+ group compared to the A‐T‐ and A+T‐ groups across all biomarkers’ measurements, with the A+T+ group always showing a higher rate of progression than the other two groups (post‐hoc chi‐square analyses; p<0.05).ConclusionAbnormal levels of Aß and tau plasma biomarkers can help predict near‐ term progression to MCI. When plasma thresholds are derived based on PET data, however, plasma biomarkers have a slightly lower specificity than PET and CSF biomarkers, and both plasma and CSF biomarkers are less sensitive than PET biomarkers.

A multivariate MRI model of Alzheimer’s disease risk is associated with clinical diagnosis, PET imaging, and plasma biomarkers in a mixed dementia sample

AbstractBackgroundWe sought to validate two structural MRI‐based brain health models: Spatial Pattern of Atrophy for REcognition of Alzheimer’s disease (SPARE‐AD) and SPARE‐Brain Age Gap (SPARE‐BAG), which estimates the discrepancy between biological brain age and chronological age. These models' generalization to non‐amnestic AD (naAD) syndromes and associations with positron emission tomography (PET) and plasma biomarkers remain underinvestigated. We hypothesized that SPARE‐AD scores in naAD would be lower (less abnormal) than in amnestic AD (aAD) but elevated (more abnormal) relative to controls; and that SPARE‐AD but not SPARE‐BAG scores would be associated with PET and plasma biomarkers of AD.MethodSPARE‐AD and SPARE‐BAG scores were estimated for each of 1607 MRI scans from 277 cognitively normal adults (62.8% female; mean age = 69.5 years) and 902 clinical participants (54.2% female; mean age = 73.1 years), including 585 with amnestic mild cognitive impairment (aMCI) or aAD; 56 with naAD syndromes; 28 with vascular disease; 28 with Lewy body disorders (LBD); 18 with suspected frontotemporal lobar degeneration (FTLD); 56 with non‐amnestic MCI of uncertain etiology; and 131 with other clinical diagnoses. We used mixed effects models adjusting for age, sex, and global cognition to test group differences in SPARE‐AD and SPARE‐BAG. Additionally, we assessed associations with tau (n = 122) and amyloid‐beta (n = 199) PET imaging and plasma‐based phosphorylated tau‐181 (p‐tau181) and glial fibrillary acidic protein (GFAP) (n = 358).ResultSPARE‐AD scores were elevated vs. controls in aMCI/aAD, naAD, vascular disease, FTLD, and naMCI (all p<0.003) but not in LBD or other diagnoses (p>0.1). NaAD patients had lower SPARE‐AD (p<0.02) but higher SPARE‐BAG scores (p<0.02) than aMCI/aAD patients. SPARE‐AD scores were positively associated with mean cortical tau PET uptake, amyloid PET positivity, and plasma p‐tau181 and GFAP (all p<0.001). In contrast, SPARE‐BAG scores were not associated with PET or plasma biomarkers (all p>0.05).ConclusionSPARE‐AD values for naAD syndromes were intermediate between those of controls and aMCI/AD patients, likely reflecting divergent, partially overlapping cortical atrophy relative to aAD. PET and plasma biomarkers of AD neuropathologic change were associated with SPARE‐AD but not with SPARE‐BAG scores, suggesting SPARE‐BAG reflects age‐related atrophy that is largely independent of AD.

Connected speech efficiency and lexical diversity are associated with PET amyloid and tau in a cognitively unimpaired sample

AbstractBackgroundChanges in connected speech (CS; language used in everyday conversations) have been documented throughout the Alzheimer’s disease (AD) spectrum, including the very early stages of disease. Our group identified four factors comprised of 10 measures of CS: fluency, semantic content, lexical diversity, and grammatical complexity. We demonstrated that fluency and semantic content were associated with subclinical cognitive decline (Mueller et al., 2018a). However, the relationship between these connected speech factors and AD biomarkers in preclinical AD is unknown.MethodCognitively unimpaired (CU) Wisconsin Registry for Alzheimer’s Prevention participants with positron emission tomography (PET) amyloid (A) and tau (T) were identified; 26 were A+/T+; an equal number matched 1:1 using nearest neighbor propensity score matching for age, sex, literacy, and race were selected from A‐/T‐ and A+/T‐ subsets (n = 78). A priori power calculation based on similar matched designs revealed >80% power to detect a medium effect size. We analyzed CS samples from a picture description task (Cookie Theft) at the neuropsychological visit closest to the most recent PET scans (median visit number = 6). Language measures were extracted from transcripts and transformed into standardized z‐scores that were used to create the factors (details in Mueller et al. (2018b)). ANOVA models investigated whether factor scores and two exploratory individual measures of CS efficiency (content information units per minute (CIU/Min) and semantic unit idea density (SUID)) differed across PET biomarker profiles (A‐/T‐ = reference group). Post‐hoc pairwise comparisons were then completed, and Cohen’s d characterized effect sizes.ResultThe mean(sd) years between CS sample and PET scan was 2.3(1.8) for amyloid and 2.1(1.7) for tau (Table 1). The lexical factor was associated with PET biomarker status, such that participants who were A+/T+ had lower lexical diversity than the A‐/T‐ group. Lower SUID was associated with both A+/T‐ and A+/T+ classification (Figure 1). Associations did not change when analyses were repeated without outliers. Effect sizes were highest for SUID (Table 2).ConclusionOf four previously derived language factors, lexical diversity was associated with PET biomarker status. However, a measure of connected speech efficiency (SUID) was also associated with biomarker status in this preclinical, CU sample. Replication in additional cohorts is needed.

Connected speech efficiency and lexical diversity are associated with PET amyloid and tau in a cognitively unimpaired sample

AbstractBackgroundChanges in connected speech (CS; language used in everyday conversations) have been documented throughout the Alzheimer’s disease (AD) spectrum, including the very early stages of disease. Our group identified four factors comprised of 10 measures of CS: fluency, semantic content, lexical diversity, and grammatical complexity. We demonstrated that fluency and semantic content were associated with subclinical cognitive decline (Mueller et al., 2018a). However, the relationship between these connected speech factors and AD biomarkers in preclinical AD is unknown.MethodCognitively unimpaired (CU) Wisconsin Registry for Alzheimer’s Prevention participants with positron emission tomography (PET) amyloid (A) and tau (T) were identified; 26 were A+/T+; an equal number matched 1:1 using nearest neighbor propensity score matching for age, sex, literacy, and race were selected from A‐/T‐ and A+/T‐ subsets (n = 78). A priori power calculation based on similar matched designs revealed >80% power to detect a medium effect size. We analyzed CS samples from a picture description task (Cookie Theft) at the neuropsychological visit closest to the most recent PET scans (median visit number = 6). Language measures were extracted from transcripts and transformed into standardized z‐scores that were used to create the factors (details in Mueller et al. (2018b)). ANOVA models investigated whether factor scores and two exploratory individual measures of CS efficiency (content information units per minute (CIU/Min) and semantic unit idea density (SUID)) differed across PET biomarker profiles (A‐/T‐ = reference group). Post‐hoc pairwise comparisons were then completed, and Cohen’s d characterized effect sizes.ResultThe mean(sd) years between CS sample and PET scan was 2.3(1.8) for amyloid and 2.1(1.7) for tau (Table 1). The lexical factor was associated with PET biomarker status, such that participants who were A+/T+ had lower lexical diversity than the A‐/T‐ group. Lower SUID was associated with both A+/T‐ and A+/T+ classification (Figure 1). Associations did not change when analyses were repeated without outliers. Effect sizes were highest for SUID (Table 2).ConclusionOf four previously derived language factors, lexical diversity was associated with PET biomarker status. However, a measure of connected speech efficiency (SUID) was also associated with biomarker status in this preclinical, CU sample. Replication in additional cohorts is needed.

Are Digital Markers of Everyday Driving Comparable to Fluid Biomarkers in Identifying Preclinical Alzheimer Disease?

AbstractBackgroundPreclinical Alzheimer’s disease (AD) may have a subtle functional signature reflected in changes in everyday driving behaviour. Driving has the potential to serve as a digital marker for AD when captured continuously and characterized accurately. This study directly compares the diagnostic performance of digital markers of everyday driving, cerebrospinal fluid (CSF), and blood biomarkers in detecting amyloid deposition in AD, using amyloid positron emission tomography (PET) as the “gold standard”.MethodParticipants were enrolled in a longitudinal study on driving and preclinical AD biomarkers at Washington University School of Medicine. The Driving Real‐World In‐Vehicle Evaluation System (DRIVES) Project uses in‐vehicle GPS dataloggers to collect daily driving among cognitive normal drivers. This study included 121 drivers (aged 65+) with complete blood, CSF, and PET biomarker data. We employed three artificial neural network (ANN) to examine the relationship between everyday driving and PET‐amyloid status. The first model solely included driving features. The second ANN model (i.e., “non‐intrusive” model) added age and education level as additional features. The third model included all of the previous features plus APOE e4 status. Plasma Aß42/Aß40<0.1013 and CSF Aß42/Aß40<0.0673 were used to detect PET‐amyloid positivity. To compare the performance of the ANN models and the CSF and plasma biomarkers, area under the receiver operating curve (AUC) from 5‐fold cross‐validation were calculated.ResultIndividuals who were PET‐amyloid positive (n = 46) were more likely to be older (p<.05) and carry an APOE e4 allele (p<.0001). The two groups did not differ in sex or education. In predicting PET‐amyloid positivity, the five most important driving features were the number of left turns per mile, 80th percentile of jerk, minimum vehicle speed, speed variability, and the number of speeding incidents. The CSF biomarker achieved the highest performance (AUC = 0.96±0.04), followed by the model with driving, age, education and APOE e4 status (AUC = 0.88±0.05). The model with only driving features achieved lower performance (AUC = 0.74±0.07), while the non‐intrusive ANN model achieved comparable performance to the plasma biomarker (AUC: 0.82±0.11vs.0.83±0.12).ConclusionDigital markers of everyday driving along with age and education level offer a non‐intrusive and scalable diagnostic tool for preclinical AD that provides ongoing assessments.

PET biomarkers in behavioral variant Frontotemporal dementia: analysis of an Argentine cohort.

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by early and progressive changes in behavior, emotional processing and executive control. This entity represents a diagnostic challenge in which positron emission tomography (PET) may play a key role in the diagnosis and follow‐up in vivo with a minimally invasive method. The aim of this work is to evaluate PET biomarkers in a cohort of patients with a clinical diagnosis of bvFTD.Method21 normal controls (NC: 64 ± 9 years) and 20 patients with a diagnosis of probable bvFTD (65 ± 7 years) were evaluated by: neurological, neuropsychological, neuropsychiatric evaluation and PET imaging biomarkers: [18F]‐FDG, [18F]‐AV1451 (TAU), [11C]‐PIB. For neuroimaging processing and analysis, they were spatially normalized to an FDG template. Group comparisons (voxel‐based) of each biomarker were performed by t‐test (SPM12) using cerebellar gray matter as reference tissue, and for inter‐biomarker uncoupling comparison a covariate of uptake in total cortex was used.ResultIn the statistical comparison between NC vs. bvFTD groups (p<0.05), hypometabolism is observed at the frontotemporal level and hypermetabolism in the precentral region (FDG). Amyloid marker (PIB) uptake shows no significant difference between groups in much of the cortex, except in the precentral region. TAU uptake shows a significant difference, greater in bvFTD, at frontal, parietal and precuneus levels. In the uncoupling between FDG and TAU biomarkers, it is observed that hypometabolism is related to an increase in TAU uptake in medial and inferior temporal regions. Differences between PIB and TAU are mainly observed in frontotemporal regions. There was an association between clinical symptoms (mainly apathy) and the anatomical distribution of [18F]‐FDG, [18F]‐AV1451 radiotracers (TAU).ConclusionPET biomarkers are a valuable tool in the diagnosis of bvFTD. The [11C]‐PIB may be of paramount importance in the differential diagnosis of FTvc FTD with Alzheimer’s disease. FDG is a very sensitive biomarker of neuronal metabolism and its variations, sometimes losing specificity. Advances in tracers such as [18F]‐AV1451 (TAU) can provide important information on the underlying neuropathological process. The combined use of these tools brings us closer to understanding the biological phenomena behind the cardinal symptoms of bvFTD.

40 Positive and Negative Emotional Outcomes Following Alzheimer’s Disease Biomarker Disclosure in Cognitively Symptomatic Older Adults

Objective:There are many potential benefits of early identification of those with Alzheimer’s disease (AD), including more opportunity for early intervention to slow AD progression (e.g., treatment, lifestyle changes, etc.) and to plan for the future. Positron emission tomography (PET) scans for abnormal amyloid and tau are commonly conducted in research settings. Despite strong interest in learning AD biomarker results, participants rarely receive their research data, in part due to concern about the possibility of undue distress based on results. We aimed to explore both positive and negative emotional reactions following PET biomarker disclosure as a function of result received.Participants and Methods:Forty-three older adults (age = 72.0±6.21 years, education = 16.5±2.62 years, 49% Female, 88% White Non-Hispanic) completed PET amyloid and tau testing and disclosure. Sixty-three percent were diagnosed with mild cognitive impairment (MCI) while the remainder of participants were diagnosed with Dementia Alzheimer’s type (DAT). Participants completed pre-disclosure biomarker education and a decisional capacity assessment followed by baseline measures. Participants then completed a disclosure session where they received personal PET amyloid and tau results on an elevated vs. not elevated scale for each ligand. Results were discussed in relation to presence/absence of Alzheimer’s disease, how the result relates to their cognitive difficulties, and risk of developing Dementia-Alzheimer’s Type. At baseline (pre-disclosure), immediately post-disclosure, and 1-week post-disclosure, participants completed the Beck Anxiety Inventory (BAI), The Geriatric Depression Scale - 15 Item (GDS-15), Impact of Neuroimaging in AD (INI-AD) Scale, and the Positive and Negative Affective Scale - Short Form (PANAS-SF). All questionnaires were modified to apply to Alzheimer’s disease and related experiences.Results:Of the 43 participants who participated in disclosure, 74% received biomarker positive results (either A+T- or A+T+); all others were biomarker negative. We conducted a series of mixed analysis of variance (ANOVA) tests to determine the effect of disclosure and biomarker status for each of the outcomes of interest. Neither the effect of time nor the time by biomarker status interaction was significant for any of the outcomes (all p>.05). The main effect of biomarker status was significant for BAI (F(1)=5.12, p=.031, n,p2=.146) and INI-AD Distress (F(1)=12.70, p=.001, np2=.241) and Positive (F(1)=34.57, p<.001, np2=.464) subscale scores with A+T-/A+T+ participants reporting higher negative affect than those who were A-/T-; however, even among biomarker positive individuals, scores did not exceed clinical thresholds. GDS-15, PANAS-Negative and Positive Subscale scores did not differ significantly by biomarker status (all p>.05) and no significant adverse events occurred following disclosure. Additionally, no participants cited regret about receiving their results.Conclusions:While disclosure of biomarker positivity may result in mild increases in acute anxiety or distress, or fewer positive emotions, it does not result in clinically significant emotional reactions and was not associated with regret. Overall, findings are consistent with literature indicating safety of biomarker disclosure procedures for symptomatic individuals. Future research should follow participants over longer periods to evaluate the impacts of biomarker disclosure.

Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-β/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aβ PET and CSF p-tau181/Aβ42 were most consistent with Aβ pathology, while tau PET and CSF p-tau181/Aβ42 were most consistent with tau pathology.

Clinical Radiosynthesis and Translation of [18F]OP-801: A Novel Radiotracer for Imaging Reactive Microglia and Macrophages.

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

Cerebrospinal fluid and positron-emission tomography biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis.

The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and undergoes substantial neuronal loss in Alzheimer's disease and Parkinson's disease. While a coherent picture of structural decline in post-mortem and in vivo MRI measures seems to emerge, whether this translates into a consistent decline in available noradrenaline levels is unclear. We conducted a meta-analysis of noradrenergic differences in Alzheimer's disease dementia and Parkinson's disease using CSF and PET biomarkers. CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol levels as well as noradrenaline transporters availability, measured with PET, were summarized from 26 articles using a random-effects model meta-analysis. Compared to controls, individuals with Parkinson's disease showed significantly decreased levels of CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol, as well as noradrenaline transporters availability in the hypothalamus. In Alzheimer's disease dementia, 3-methoxy-4-hydroxyphenylglycol but not noradrenaline levels were increased compared to controls. Both CSF and PET biomarkers of noradrenergic dysfunction reveal significant alterations in Parkinson's disease and Alzheimer's disease dementia. However, further studies are required to understand how these biomarkers are associated to the clinical symptoms and pathology.

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy.

This study aimed to assess whether biomarkers related to amyloid, tau, and neurodegeneration can accurately predict Alzheimer's disease (AD) neuropathology at autopsy in early and late clinical stages. We included 100 participants who had ante mortem biomarker measurements and underwent post mortem neuropathological examination. Based on ante mortem clinical diagnosis, participants were divided into non-dementia and dementia, as early or late clinical stages. Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) amyloid beta (Aβ)42/phosphorylated tau (p-tau)181 showed excellent performance in differentiating autopsy-confirmed AD and predicting the risk of neuropathological changes in early and late clinical stages. However, CSF Aβ42 performed better in the early clinical stage, while CSF p-tau181, CSF t-tau, and plasma p-tau181 performed better in the late clinical stage. Our findings provide important clinical information that, if using PET, CSF, and plasma biomarkers to detect AD pathology, researchers must consider their differential performances at different clinical stages of AD. Amyloid PET and CSF Aβ42/p-tau181 were the most promising candidate biomarkers for predicting AD pathology. CSF Aβ42 can serve as a candidate predictive biomarker in the early clinical stage of AD. CSF p-tau181, CSF t-tau, and plasma p-tau181 can serve as candidate predictive biomarkers in the late clinical stage of AD. Combining APOE ε4genotypescan significantly improve the predictive accuracy of AD-related biomarkers for AD pathology.