PET Biomarkers Research Articles

Radiosynthesis and Analysis of (S)-4-(3-[18F]Fluoropropyl)-L-Glutamic Acid

Purpose(S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is an L-glutamate derivative used as a PET biomarker to assess intracellular redox status in vivo through targeting of the cystine/glutamate antiporter protein, xc− transporter. In this report, we describe a radiosynthesis of [18F]FSPG for use in PET studies that address specific challenges in relation to the radiotracer purity, molar activity, and quality control testing methods.ProceduresThe radiosynthesis of [18F]FSPG was performed using a customised RNPlus Research automated radiosynthesis system (Synthra GmbH, Hamburg, Germany). [18F]FSPG was labelled in the 3-fluoropropylmoiety at the 4-position of the glutamic acid backbone with fluorine-18 via substitution of nucleophilic [18F]fluoride with a protected naphthylsulfonyloxy-propyl-L-glutamate derivative. Radiochemical purity of the final product was determined by radio HPLC using a new method of direct analysis using a Hypercarb C18 column.ResultsThe average radioactivity yield of [18F]FSPG was 4.2 GBq (range, 3.4–4.8 GBq) at the end of synthesis, starting from 16 GBq of [18F]fluoride at the end of bombardment (n = 10) in a synthesis time of 50 min. The average molar activity and radioactivity volumetric concentration at the end of synthesis were 66 GBq µmol−1 (range, 48–73 GBq µmol−1) and 343–400 MBq mL−1, respectively.ConclusionStability tests using a 4.6 GBq dose with a radioactivity volumetric concentration of 369 MBq mL−1 at the end of synthesis showed no observable radiolysis 3 h after production. The formulated product is of high radiochemical purity (> 95%) and higher molar activity compared to previous methods and is safe to inject into mice up to 3 h after production.

Validation of a continuous model of amyloid‐β CSF/PET discordance across cohorts and PET tracers

AbstractBackgroundRecently, we provided evidence that discordance in CSF vs. PET amyloid‐β biomarkers represents a natural phase in the progression of amyloid‐β pathology, with either CSF or PET biomarkers becoming abnormal first, based on well‐validated cut‐offs. We found that CSF‐/PET+ individuals had lower prevalence of APOE‐ε4 genotype and slower rate of amyloid‐β PET accumulation compared with CSF+/PET‐ individuals [1]. Given the methodological limitations of binary cut‐offs, here we aimed to validate a continuous model of imbalance in CSF vs. PET amyloid‐β biomarkers across cohorts and tracers, and to investigate biological factors underlying discordance in CSF and PET results.MethodThe study included n=944 participants from two independent cohorts: ADNI and AMYPAD. We selected n=822 individuals (73.0±7.4 yr‐old, 53% female, 45% APOE‐ε4 carriers, 16.3±2.6 yr‐education) from ADNI, ranging from cognitively‐normal to demented, with global cortical 18F‐florbetapir‐PET and CSF‐Aβ42 measurements available within 3‐months; all participants also had CSF‐Aβ38 and CSF‐Aβ40 available. We also selected n=112 individuals (65.6±7.0 years, 59.8% female, 30.6% APOE‐ε4 carriers, 15±3.5 yr‐education) ranging from cognitively‐normal to MCI from the AMYPAD Prospective and Natural History Study (PNHS) cohort with CSF‐Aβ42 and global cortical 18F‐flutemetamol (n=75) or 18F‐florbetaben (n=37) PET available within one‐year, expressed in Centiloids. In each cohort, we iteratively fitted the CSF/PET cross‐sectional data to a hyperbolic regression model with three parameters, by minimizing the Euclidean distance of the experimental points to the fitted line (Fig. 1). For each individual, we derived a measure of imbalance based on standardized residuals, with zimbalance>0 reflecting PET‐over‐CSF imbalance (zimbalance<0 reflecting CSF‐over‐PET imbalance).ResultsThe hyperbolic model adequately fitted the CSF/PET data across cohorts and tracers (pseudo‐R2>0.90, Fig. 1). In ADNI, greater zimbalance (PET‐over‐CSF imbalance) was associated with lower APOE‐e4 prevalence, and higher levels of CSF‐Aβ42, CSF‐Aβ40 and CSF‐Aβ38, corrected for demographics and disease stage. Studies in the AMYPAD cohort are ongoing.ConclusionWe tested a continuous model of amyloid‐β CSF vs. PET imbalance across cohorts and PET tracers. Imbalance in CSF vs. PET amyloid‐β values carries meaningful biological and genetic information, which allows to identify heterogeneous pathological trajectories in the AD continuum, with implications for clinical trials.[1] Sala et al. (2021) Mol. Psychiatry 26(10):5864‐5874

Simultaneous Mass Spectrometric quantification of multiple p‐tau species in plasma – findings along the Alzheimer´s disease continuum

AbstractBackgroundBlood phosphorylated tau (p‐tau) species at positions 181, 217 and 231 have been demonstrated accurate biomarkers of Alzheimer´s disease pathology. Comparisons to assess the performance of each phosphorylation along the Alzheimer´s disease (AD) continuum rely on the use of different immunoassays. In the current study, we simultaneously quantified the plasma concentration of six different phosphorylated (p‐tau 181, 199, 202, 205, 217 and 231), and two non‐phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method.MethodWe analysed a total of 224 samples from two centres, the TRIAD cohort (Canada) and the BioCogBank Paris Lariboisière cohort (France). Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non‐phospho‐tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. Group‐level comparisons were carried with non‐parametric tests. Cross‐sectional associations between plasma tau biomarkers and Aβ and tau PET were investigated using the locally estimated scatterplot smoothing (LOESS) method for local polynomial regression. Voxel‐wise correlations were performed between plasma and PET biomarkers using Rminc.ResultP‐tau231 levels were significantly increased in amyloid positive and tau negative (A+T‐) individuals compared to A‐T‐ (stratified by CSF biomarkers). Increases in p‐tau217 and p‐tau205 emerged later in the AD continuum, only when tau pathology was present (A+T+). Plasma p‐tau217, p‐tau231 and p‐tau205 were the site‐specific phosphorylations that showed higher correlations with Tau PET (Braak I‐VI) (R=0.7 p<0.0001; R=0.53 p<0.0001; and R=0.53 p<0.0001; respectively) and with Aβ PET (R=0.66 p<0.0001; R=0.56 p<0.0001; R=0.45 p<0.0001, respectively). LOESS analysis revealed that plasma p‐tau231 increases earlier in the disease progression, followed by p‐tau217 and p‐tau205, which showed a progressive increase along Braak stages and amyloid centiloid. Voxel‐wise analysis for tau PET were highest with p‐tau205 with associations in in the inferior, medial, and lateral temporal regions. For Aβ PET, p‐tau217 and p‐tau205 showed the highest associations with frontal, precuneus, posterior cingulate and temporal cortices.ConclusionOur results indicate that plasma p‐tau217, p‐tau231 and p‐tau205 are the site‐specific phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum.

Stress, anxiety and depression in older adults at increased risk for cognitive decline: association with biomarkers and sex/gender differences

AbstractBackgroundAnxious depressive symptomatology and stress are associated with cognitive decline. Recent evidence suggests a relation between these factors and Alzheimer’s disease (AD) pathophysiology early in the continuum. With the current increases in anxiety, depression and stress due to the Covid19 pandemic ‐ notably in women ‐ unrevealing the biological mechanisms underlying these associations with a sex/gender approach appears fundamental.MethodWe included a total of 1170 participants in a series of observational cohort studies. Participants were cognitively unimpaired with increased risk of AD dementia (family history, APOE ε4, subjective cognitive decline). We investigated stressful life events with a lifespan perspective, stress perception, and changes in anxiety/depression in late life in relation to CSF, PET and MRI biomarkers of AD pathologies, neuroinflammation and brain atrophy. To that end, we performed multiple regression models adjusted by age, sex and education level. We also carried out stratified analyses by sex and explored sex differences in lifestyle and anxious‐behaviors (e.g., eating and sleep patterns).ResultThe accumulation of stressful life events as well as late‐life anxious depressive symptoms were associated with neuroinflammation markers, notably in women. Midlife stress was associated with increased tau and brain atrophy, together with lifetime history of anxiety/depression. In late life, amyloid positivity predicted longitudinal increases in anxiety and depression in the face of stressors, i.e., the covid19 pandemic, in women. Stress perception was not itself associated with any biomarker tested but mediated the increases in anxiety/depression. Women showed higher anxiety/depression and stress‐perception than men. While sex‐differences were identified in eating and sleep patterns, these did not explain the reported associations.ConclusionsOur results suggest that mental health factors and stress should be tackled from a life‐span and sex/gender perspective in people at risk for cognitive decline (Fig1): midlife stress may enhance tau pathology and brain atrophy. Accumulation of stress and anxiety/depression may enhance neuroinflammation pathways in women as well as brain atrophy. Once amyloid is present, women may be more prone to show increases in anxiety and depression in the face of stressors. Finally, stress‐perception represents an intervenable factor that may prevent increases in anxiety and depression.

Convergent and criterion validity of a computer adaptive self‐administered word list memory test and the Mayo Test Drive composite: correlations with traditional measures and group difference by PET imaging biomarker status in persons without dementia.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.

Composite SUVR: a new method for boosting Alzheimer’s disease monitoring and diagnostic performance, applied to tau PET

AbstractBackgroundAbnormal brain tau protein accumulation is strongly linked to multiple neurodegenerative disorders. Currently, brain tau pathology is quantified in vivo using tau PET by calculating the Standardized Uptake Value Ratio (SUVR) of target and reference regions of interest (ROIs).Recent work (Schwarz et al., 2021) in Alzheimer’s Disease (AD) explored various target and reference ROIs to report performance of SUVR as a biomarker for diagnosis, disease monitoring, and clinical trial efficacy/eligibility (sample size estimate, SSE). Here we introduce a new method and biomarker: Composite SUVR (CUVR).MethodsWe analyzed longitudinal SUV data from ADNI in the available 103 participants having three or more tau PET scans ([18F]AV‐1451): 58 cognitively normal (CN); 21 mild cognitive impairment; 24 probable AD. In the spirit of SUVR and statistical ROIs (Chen, et al., NeuroImage 2010), we calculate CUVR as the SUV ratio of two composite regions. Our novel method is that the composite regions are determined by a genetic algorithm that searches the possible 3^96 combinations of regions from FreeSurfer’s default atlas. We compare performance of SUVR with CUVR.Performance metrics follow Schwarz et al.: a linear mixed‐effects model quantifies longitudinal group separation by tau accumulation rate (t statistic between fixed effects for CN and AD) and longitudinal precision (model residuals’ standard deviation). CUVR and SUVR values were log‐transformed before model fitting.We calculated SSE for a hypothetical clinical trial designed for 80% power to reduce tau PET accumulation by 20% (vs. placebo) in non‐CN individuals.ResultsOur method identified a CUVR biomarker involving 60 regions. Figure‐1 shows the vast performance improvement of CUVR versus the best‐performing SUVR (inferior‐temporal target; eroded subcortical white matter reference). Group separation improved by 2.9x (t = 9.57 vs 3.32); longitudinal precision by 6.5x (residual std = 0.331% vs 2.14%); and CUVR required a smaller sample size by 3.9x (83 vs 318).ConclusionsOur simple data‐driven approach discovered a new tau PET biomarker called CUVR. Experimental results show state‐of‐the‐art longitudinal group separation, longitudinal precision, and clinical trial enrichment. The remarkable performance improvements provide compelling evidence for using CUVR for both eligibility and efficacy in Alzheimer’s disease clinical trials, particularly of anti‐tau therapies.

A new flortaucipir PET biomarker based on graph theory for early detection of CTE in former American football players

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.MethodThe graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.ResultEntorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).ConclusionWhile there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.

The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer’s Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

BackgroundScreening procedures for early Alzheimer’s disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain.ObjectivesCross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and β-amyloid (Aβ) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD.DesignSecondary analyses of cross-sectional and longitudinal clinical trial data.SettingMulti-center international clinical trials.ParticipantsIndividuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aβ positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331).MeasurementsCross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aβ positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL).ResultsLower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aβ positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel).ConclusionsCutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aβ positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.

Gray matter hypoperfusion is a late pathological event in the course of Alzheimer’s disease

Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.

Discordant Amyloid Status Diagnosis in Alzheimer's Disease.

Early and accurate Alzheimer's disease (AD) diagnosis has evolved in recent years by the use of specific methods for detecting its histopathological features in concrete cases. Currently, biomarkers in cerebrospinal fluid (CSF) and imaging techniques (amyloid PET) are the most used specific methods. However, some results between both methods are discrepant. Therefore, an evaluation of these discrepant cases is required. The aim of this work is to analyze the characteristics of cases showing discrepancies between methods for detecting amyloid pathology. Patients from the Neurology Department of La Fe Hospital (n = 82) were diagnosed using both methods (CSF biomarkers and amyloid-PET). Statistical analyses were performed using logistic regression, and sex and age were included as covariables. Additionally, results of standard neuropsychological evaluations were taken into account in our analyses. The comparison between CSF biomarker (Aβ42) and amyloid PET results showed that around 18% of cases were discrepant-mainly CFS-negative and PET-positive cases had CSF levels close to the cut-off point. In addition, a correlation between the episodic memory test and CSF biomarkers levels was observed. However, the same results were not obtained for other neuropsychological domains. In general, CSF- and PET-discrepant cases showed altered episodic memory in around 66% of cases, while 33% showed normal performance. In common clinical practice at tertiary memory centers, result discrepancies between tests of amyloid status are far more common than expected. However, episodic memory tests remain an important support method for AD diagnosis, especially in cases with discrepant results between amyloid PET and CSF biomarkers.

Circulating Amyloid-β and Methionine-Related Metabolites to Predict the Risk of Mild Cognitive Impairment: A Nested Case-Control Study.

The high cost, limited availability, and perceived invasiveness of amyloid PET and cerebrospinal fluid biomarkers limit their use for the diagnosis of Alzheimer's disease. The present study aimed to assess the associations of mild cognitive impairment (MCI) with circulating amyloid-β (Aβ), methionine circulating metabolites (MCMs), and their downstream products, and to develop a nomogram based on these easily accessible blood indexes for the individualized prediction of MCI risk in older adults. In this nested case-control study, we recruited 74 MCI patients and, for each, 3 matched controls (n = 222) within the context of the Tianjin Elderly Nutrition and Cognition (TENC) cohort, a population-based prospective study in China. Concentrations of Aβ, MCMs, and their circulating downstream factors (i.e., leukocyte telomere length and inflammatory cytokines) were evaluated in fasting blood sample using standard procedures. We constructed a nomogram for MCI harnessed multivariable logistic models incorporating variables selected in the Lasso regression. Among the many biomarkers examined, the final prediction nomogram retained only 3 factors: Aβ42/Aβ40 ratio, Hcy, and SAM/SAH ratio. The model achieved favorable discrimination, with a C-statistic of 0.75 (95% confidence interval 0.69-0.81) in internal validation after adjustment of optimism. The calibration accuracy was satisfactory; the Brier score of the model was 0.161 in internal validation after adjustment of optimism. his study presents an individualized prediction nomogram incorporating only three blood biomarkers (i.e., Aβ42/Aβ40 ratio, Hcy, and SAM/SAH ratio), which can be conveniently utilized to facilitate early identification and the development of high-risk prevention strategies for MCI in older adults.

Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.

Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints. The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aβ42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aβ42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances. In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

The RSNA QIBA Profile for Amyloid PET as an Imaging Biomarker for Cerebral Amyloid Quantification.

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of β-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging.

Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies.

Topographical distribution of white matter hyperintensities (WMH) are hypothesized to vary by cerebrovascular risk factors. We used an unbiased pattern discovery approach to identify distinct WMH spatial patterns and investigate their association with different WMH etiologies. We performed a cross-sectional study on participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify spatially distinct WMH distribution patterns using voxel-based spectral clustering analysis of aligned WMH probability maps. We included all participants from the ADNI Grand Opportunity/ADNI 2 study with available baseline 2D-FLAIR MRI scans, without history of stroke or presence of infarction on imaging. We evaluated the associations of these WMH spatial patterns with vascular risk factors, amyloid-β PET, and imaging biomarkers of cerebral amyloid angiopathy (CAA), characterizing different forms of cerebral small vessel disease (CSVD) using multivariable regression. We also used linear regression models to investigate whether WMH spatial distribution influenced cognitive impairment. We analyzed MRI scans of 1,046 ADNI participants with mixed vascular and amyloid-related risk factors (mean age 72.9, 47.7% female, 31.4% hypertensive, 48.3% with abnormal amyloid PET). We observed unbiased partitioning of WMH into 5 unique spatial patterns: deep frontal, periventricular, juxtacortical, parietal, and posterior. Juxtacortical WMH were independently associated with probable CAA, deep frontal WMH were associated with risk factors for arteriolosclerosis (hypertension and diabetes), and parietal WMH were associated with brain amyloid accumulation, consistent with an Alzheimer disease (AD) phenotype. Juxtacortical, deep frontal, and parietal WMH spatial patterns were associated with cognitive impairment. Periventricular and posterior WMH spatial patterns were unrelated to any disease phenotype or cognitive decline. Data-driven WMH spatial patterns reflect discrete underlying etiologies including arteriolosclerosis, CAA, AD, and normal aging. Global measures of WMH volume may miss important spatial distinctions. WMH spatial signatures may serve as etiology-specific imaging markers, helping to resolve WMH heterogeneity, identify the dominant underlying pathologic process, and improve prediction of clinical-relevant trajectories that influence cognitive decline.

Atypical Alzheimer's disease phenotypes with normal or borderline PET biomarker profiles.

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer's disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [11C] Pittsburgh compound B, [18F] flortaucipir and [18F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: (i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); (ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and (iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of cortico-basal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~ 8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD.

Focal amyloid and asymmetric tau in an imaging-to-autopsy case of clinical primary progressive aphasia with Alzheimer disease neuropathology

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo 18F-florbetapir amyloid PET and 18F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months. Florbetapir and flortaucpir PET standard uptake value ratios (SUVRs) were quantified from 8 left and right hemisphere brain regions with stereological quantification of amyloid plaques and NFTs from corresponding postmortem sections. Pearson’s correlations and measures of asymmetry were used to examine relationships between imaging and autopsy measurements. The three visits prior to death revealed decline of language measures, with marked progression of atrophy. Florbetapir PET presented with an atypical focal pattern of uptake and showed a significant positive correlation with postmortem amyloid plaque density across the 8 regions (r = 0.92; p = 0.001). Flortaucipir PET had a left-lateralized distribution and showed a significant positive correlation with NFT density (r = 0.78; p = 0.023). Flortaucipir PET and NFT density indicated a medial temporal lobe sparing presentation of ADNC, demonstrating that AD does not always target the medial temporal lobe. This study adds additional evidence, in a non-amnestic phenotype of ADNC, that there is a strong correlation between AD PET biomarkers, florbetapir and flortaucipir, with quantitative neuropathology. The atypical and focal presentation of plaque density and florbetapir PET uptake suggests not all amyloid pathology presents as diffuse across neocortex.

18F-FDG PET, cognitive, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment

18F-FDG PET, cognitive, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment

Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer's disease.

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

18F-FDG PET, cognitive functioning, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment

IntroductionDysregulation of cerebral glucose consumption, alterations in cerebrospinal fluid (CSF) biomarkers, and cognitive impairment have been reported in patients with obstructive sleep apnoea (OSA). On these bases, OSA has been considered a risk factor for Alzheimer’s disease (AD). This study aimed to measure cognitive performance, CSF biomarkers, and cerebral glucose consumption in OSA patients and to evaluate the effects of continuous positive airway pressure (CPAP) treatment on these biomarkers over a 12-month period.MethodsThirty-four OSA patients and 34 controls underwent 18F-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET), cognitive evaluation, and CSF analysis. A subgroup of 12 OSA patients treated with beneficial CPAP and performing the 12-month follow-up was included in the longitudinal analysis, and cognitive evaluation and 18F-FDG PET were repeated.ResultsSignificantly reduced glucose consumption was observed in the bilateral praecuneus, posterior cingulate cortex, and frontal areas in OSA patients than controls. At baseline, OSA patients also showed lower β-amyloid42 and higher phosphorylated-tau CSF levels than controls. Increased total tau and phosphorylated tau levels correlated with a reduction in brain glucose consumption in a cluster of different brain areas. In the longitudinal analysis, OSA patients showed an improvement in cognition and a global increase in cerebral 18F-FDG uptake.ConclusionsCognitive impairment, reduced cerebral glucose consumption, and alterations in CSF biomarkers were observed in OSA patients, which may reinforce the hypothesis of AD neurodegenerative processes triggered by OSA. Notably, cognition and brain glucose consumption improved after beneficial CPAP treatment. Further studies are needed to evaluate the long-term effects of CPAP treatment on these AD biomarkers.