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Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer’s disease (AD) pathology and predicting clinical progression. In this study, we performed a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum. Methods: We included participants from the Amsterdam Dementia Cohort who underwent 18F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Ab-negative and 19 Ab-positive) and 60 Ab-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available (n 5 40). Longitudinal neuropsychological test data covering 3.2 6 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Ab status (SCD Ab-positive vs. SCD Ab-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time. Results: When discriminating between preclinical Ab status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong P . 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all P, 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, 20.02 . b, 20.12; tau PET, 20.01 . b, 20.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD (P, 0.05), but only tau PET annual changes were associated with cognitive decline. Conclusion: Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Ab pathology but that tau PET better monitors disease stage and clinical progression.

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

Purpose Dynamic positron emission tomography (PET) protocols allow for accurate quantification of [18F]flortaucipir-specific binding. However, dynamic acquisitions can be challenging given the long required scan duration of 130 min. The current study assessed the effect of shorter scan protocols for [18F]flortaucipir on its quantitative accuracy. Procedures Two study cohorts with Alzheimer’s disease (AD) patients and healthy controls (HC) were included. All subjects underwent a 130-min dynamic [18F]flortaucipir PET scan consisting of two parts (0–60/80–130 min) post-injection. Arterial sampling was acquired during scanning of the first cohort only. For the second cohort, a second PET scan was acquired within 1–4 weeks of the first PET scan to assess test-retest repeatability (TRT). Three alternative time intervals were explored for the second part of the scan: 80–120, 80–110 and 80–100 min. Furthermore, the first part of the scan was also varied: 0–50, 0–40 and 0–30 min time intervals were assessed. The gap in the reference TACs was interpolated using four different interpolation methods: population-based input function 2T4k_VB (POP-IP_2T4k_VB), cubic, linear and exponential. Regional binding potential (BPND) and relative tracer delivery (R1) values estimated using simplified reference tissue model (SRTM) and/or receptor parametric mapping (RPM). The different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, TRT of the RPM BPND and R1 values estimated using the optimal shortest scan duration was also assessed. Results RPM BPND and R1 obtained using 0–30/80–100 min scan and POP-IP_2T4k_VB reference region interpolation had an excellent correlation with the respective parametric values estimated using the original scan duration (r2 > 0.95). The TRT of RPM BPND and R1 using the shortest scan duration was − 1 ± 5 % and − 1 ± 6 % respectively. Conclusions This study demonstrated that [18F]flortaucipir PET scan can be acquired with sufficient quantitative accuracy using only 50 min of dual-time-window scanning time.

Introduction: We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern. Methods: Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age). Results: Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent). Discussion: These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve.

ObjectiveTo assess the [18F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers.MethodsWe compared regional [18F]flortaucipir binding potential (BPND) derived from a 130-minute dynamic [18F]flortaucipir PET scan in 9 (pre)symptomatic MAPT mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease.Results[18F]Flortaucipir BPND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BPND was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [18F]flortaucipir BPND in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BPND, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BPND compared to controls. The BPND values of the S320F presymptomatic mutation carrier fell within the range of controls.ConclusionPresymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [18F]flortaucipir BPND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [18F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies.

Objective The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.Methods We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (A beta) aggregation as measured by the A beta 1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for A beta production (beta-secretase 1, A beta 1-40, and A beta 1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E epsilon 4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.Results Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, A beta production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and A beta aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that A beta 1-38 in one twin correlated with A beta 1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in A beta production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that A beta production and tau levels show coordinated increases in very early AD.Interpretation Our results suggest a substantial genetic/shared environmental background contributes to both A beta and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021

SummaryA significant number of COVID-19 patients develop ‘long COVID’, a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.

Introduction: Empirical studies on effective communication for amyloid disclosure in mild cognitive impairment (MCI) are lacking. We aimed to study the impact of six communication strategies. Method: We performed a randomized controlled trial with seven randomly assigned, video-vignette conditions: six emphasizing a communication strategy and one basic condition. All showed a scripted consultation of a neurologist disclosing positive amyloid positron emission tomography (PET) scan results to an MCI patient. Healthy individuals (N = 1017; mean age ± SD 64 ± 8, 808 (79%) female) were instructed to imagine themselves in the video, answered questionnaires assessing information recall, emotional state, and behavioral intentions, and evaluate the physician/information. Results: “Risk best practice” resulted in highest free recall compared to other strategies (P

Objective Accumulation of amyloid‐β is among the earliest changes in Alzheimer’s disease (AD). Amyloid‐β positron emission tomography (PET) and Aβ 42 in cerebrospinal fluid (CSF) both assess amyloid‐β pathology in‐vivo, but 10–20% of cases show discordant (CSF+/PET− or CSF‐/PET+) results. The neuropathological correspondence with amyloid‐β CSF/PET discordance is unknown. Methods We included 21 patients from our tertiary memory clinic who had undergone both CSF Aβ 42 analysis and amyloid‐β PET, and had neuropathological data available. Amyloid‐β PET and CSF results were compared with neuropathological ABC scores (comprising of Thal (A), Braak (B), and CERAD (C) stage, all ranging from 0 [low] to 3 [high]) and neuropathological diagnosis. Results Neuropathological diagnosis was AD in 11 (52%) patients. Amyloid‐β PET was positive in all A3, C2, and C3 cases and in one of the two A2 cases. CSF Aβ 42 was positive in 92% of ≥A2 and 90% of ≥C2 cases. PET and CSF were discordant in three of 21 (14%) cases: CSF+/PET− in a patient with granulomatosis with polyangiitis (A0B0C0), CSF+/PET− in a patient with FTLD‐TDP type B (A2B1C1), and CSF‐/PET+ in a patient with AD (A3B3C3). Two CSF+/PET+ cases had a non‐AD neuropathological diagnosis, that is FTLD‐TDP type E (A3B1C1) and adult‐onset leukoencephalopathy with axonal spheroids (A1B1C0). Interpretation Our study demonstrates neuropathological underpinnings of amyloid‐β CSF/PET discordance. Furthermore, amyloid‐β biomarker positivity on both PET and CSF did not invariably result in an AD diagnosis at autopsy, illustrating the importance of considering relevant comorbidities when evaluating amyloid‐β biomarker results.

Purpose: Several studies found reduced retinal thickness on optical coherence tomography (OCT) in Alzheimer’s disease (AD), even in preclinical stages, labelling this technique of interest as biomarker. In this study, we examine retinal thickness changes in preclinical AD, as defined by cognitively normal individuals with amyloid-beta (Aβ) on positron emission tomography (PET). Methods: For this monocentre study, 145 cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the EMIF-AD PreclinAD study. At baseline, participants underwent [ 18F] flutemetamol PET that was visually rated for cortical Aβ. Binding potential was calculated as continuous measure for Aβ. Optical coherence tomography (OCT) was performed at baseline and after 22 months to assess changes in total and individual inner retinal layer thickness in the macular region (ETDRS circles) and peripapillary retinal nerve fibre layer thickness. Differences in rate of change between amyloid-beta positive and negative individuals and associations between binding potential and change in retinal thickness were evaluated. Results: Sixteen participants (11%) were positive for Aβ. Change in retinal thickness did not differ in any region between Aβ+ and Aβ− individuals. A positive association between binding potential and change in inner plexiform layer thickness was observed in the inner macular ring (beta = 1.708, CI = 0.575 to 2.841, p = 0.003). Conclusion: Aβ+ individuals did not differ in rate of change of any retinal layer compared to controls, but higher binding potential at baseline was associated with less IPL thinning over time. Optical coherence tomography (OCT) as a longitudinal screening tool for preclinical AD seems limited, but IPL changes offer leads for further research.

Purpose Visual reading of 18F-florbetapir positron emission tomography (PET) scans is used in the diagnostic process of patients with cognitive disorders for assessment of amyloid-ß (Aß) depositions. However, this can be time-consuming, and difficult in case of borderline amyloid pathology. Computer-aided pattern recognition can be helpful in this process but needs to be validated. The aim of this work was to develop, train, validate and test a convolutional neural network (CNN) for discriminating between Aß negative and positive 18F-florbetapir PET scans in patients with subjective cognitive decline (SCD). Methods 18F-florbetapir PET images were acquired and visually assessed. The SCD cohort consisted of 133 patients from the SCIENCe cohort and 22 patients from the ADNI database. From the SCIENCe cohort, standardized uptake value ratio (SUVR) images were computed. From the ADNI database, SUVR images were extracted. 2D CNNs (axial, coronal and sagittal) were built to capture features of the scans. The SCIENCe scans were randomly divided into training and validation set (5-fold cross-validation), and the ADNI scans were used as test set. Performance was evaluated based on average accuracy, sensitivity and specificity from the cross-validation. Next, the best performing CNN was evaluated on the test set. Results The sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity. Conclusion The 2D-CNN algorithm can classify Aß negative and positive 18F-florbetapir PET scans with high performance in SCD patients.

Purpose We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer’s disease (AD), by using a single dynamic [18F]flortaucipir positron emission tomography (PET) scan. Methods Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [18F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BPND) and R1, respectively. (Voxel-wise) linear regressions were used to investigate associations between BPND and/or R1 and cognition. Results Higher [18F]flortaucipir BPND was associated with lower R1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BPND was associated with worse memory, and higher lateral temporal BPND with worse executive functioning and language. Higher parietal BPND was associated with worse executive functioning, language and attention, and higher occipital BPND with lower cognitive scores across all domains. Higher frontal BPND was associated with worse executive function and attention. For [18F]flortaucipir R1, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R1 with lower language and attention scores. When [18F]flortaucipir BPND and R1 were modelled simultaneously, associations between lower R1 in the lateral temporal ROI and worse attention remained, as well as for lower parietal R1 and worse executive functioning and attention. Conclusion Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.

BACKGROUND: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

Objective: Automated voxel-based analysis methods are used to detect cortical hypometabolism typical of Alzheimer’s Disease (AD) on FDG-PET brain scans. We compared the accuracy of two clinically validated tools for their ability to identify those MCI subjects progressing to AD at followup, to evaluate the impact of the analysis method on FDG-PET diagnostic performance. Methods: SPMGrid and BRASS (Hermes Medical Solutions, Stockholm, Sweden) were tested on 131 MCI and elderly healthy controls from the EADC PET dataset. The concordance between the tools was tested by correlating the quantitative parameters (z- and t-values), calculated by the two software tools, and by measuring the topographical overlap of the abnormal regions (Dice score). Three independent expert readers blindly assigned a diagnosis based on the two map sets. We used conversion to AD dementia as the gold standard. Results: The t-map and z-map calculated with SPMGrid and BRASS, respectively, showed a good correlation (R > .50) for the majority of individual cases (128/131) and for the majority of selected regions of interest (ROIs) (98/116). The overlap of the hypometabolic patterns from the two tools was, however, poor (Dice score .36). The diagnostic performance was comparable, with BRASS showing significantly higher sensitivity (.82 versus .59) and SPMGrid showing higher specificity (.87 versus .52). Conclusion: Despite similar diagnostic performance in predicting conversion to AD in MCI subjects, the two tools showed significant differences, and the maps provided by the tools showed limited overlap. These results underline the urgency for standardization across FDG-PET analysis methods for their use in clinical practice.

Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer’s disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model’s performance to that of multiple expert nuclear medicine physicians’ readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer’s disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model’s performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. Results The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6–100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7–100) in AD, 71.4% (51.6–91.2) in MCI-AD, and 94.7% (90–99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. Conclusion Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.

IntroductionA timely diagnosis of Alzheimer’s Disease (AD) in an early stage of dementia is important to support timely access to treatment, advice, and care. The aim of this study was to estimate the diagnostic accuracy of [18F]flutemetamol PET in addition to the usual diagnostic workup for the diagnosis of AD in a memory clinic population with young onset dementia by means of a panel reference-based etiology diagnosis.Methodsin an academic memory clinic early onset dementia cohort (n=211) the nosological diagnosis was set by usual diagnostic workup and after including [18F]flutemetamol amyloid PET in a stepwise approach. To assess the change in proportion correctly diagnosed, the diagnosis with and without [18F]flutemetamol PET was related to a panel-based reference standard, serving as gold standard, consisting of 3 neurologists who relied on available clinical information over 2-year follow-up (n=152; blinded for PET).ResultsThe panel majority nosology was set as a reference diagnosis in 122 participants, leaving 30 (20%) participants with no majority reached. In 107 (88%) cases post-PET was in line with the reference, and in 103 (84%) the pre-PET diagnosis was in line with the reference. The difference was 3.3% (95% CI -3.5% to 10.1%; p=0.424).Discussion[18F]flutemetamol PET did not significantly improve the diagnostic accuracy in young patients with dementia in an academic memory clinic setting. The secondary analyses provided several indications for future research in a narrower subsample of persons with (very) high diagnostic uncertainty and to assess patient relevant health outcomes.

Background Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 APOE-ε4 carriers only. Results Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.

Background The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. Methods Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. Results Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. Conclusions These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

INTRODUCTIONPrevious work showed the in-vivo presence of retinal amyloid in AD patients using curcumin. We aimed to replicate these findings in an amyloid biomarker confirmed cohort.METHODSTwenty-six AD patients (age 66 (+9), MMSE≥17) and 14 controls (age 71(+12)) used one of three curcumin formulations: Longvida®, Theracurmin® and Novasol®.Plasma levels were determined and pre- and post-curcumin retinal fluorescence scans were visually assessed in all cases and quantitatively assessed in a subset.RESULTSVisual assessment showed no difference between AD patients and controls for pre- and post-curcumin images. This was confirmed by quantitative analyses on a subset. Mean conjugated plasma curcumin levels were 198.7 nM (Longvida®), 576.6 nM (Theracurmin®) and 1605.8 nM (Novasol®).DISCUSSIONWe found no difference in retinal fluorescence betweenamyloid confirmed AD cases and control participants, using Longvida® and two additional curcumin formulations. Additional replication studies in amyloid confirmed cohorts are needed to assess the diagnostic value of retinal fluorescence as an AD biomarker.

Objectives Determinants of cognitive functioning in individuals aged 90 years and older, the oldest-old, remain poorly understood. We aimed to establish the association of risk factors, white matter hyperintensities (WMHs), hippocampal atrophy, and amyloid aggregation with cognition in the oldest-old. Method We included 84 individuals without cognitive impairment and 38 individuals with cognitive impairment from the EMIF-AD 90+ Study (mean age 92.4 years) and tested cross-sectional associations between risk factors (cognitive activity, physical parameters, nutritional status, inflammatory markers, and cardiovascular risk factors), brain pathology biomarkers (WMH and hippocampal volume on magnetic resonance imaging, and amyloid binding measured with positron emission tomography), and cognition. Additionally, we tested whether the brain pathology biomarkers were independently associated with cognition. When applicable, we tested whether the effect of risk factors on cognition was mediated by brain pathology. Results Lower values for handgrip strength, Short Physical Performance Battery (SPPB), nutritional status, HbA1c, and hippocampal volume, and higher values for WMH volume and amyloid binding were associated with worse cognition. Higher past cognitive activity and lower body mass index were associated with increased amyloid binding, lower muscle mass with more WMH, and lower SPPB scores with more WMH and hippocampal atrophy. The brain pathology markers were independently associated with cognition. The association of SPPB with cognition was partially mediated by hippocampal volume. Discussion In the oldest-old, physical parameters, nutritional status, HbA1c, WMH, hippocampal atrophy, and amyloid binding are associated with cognitive impairment. Physical performance may affect cognition through hippocampal atrophy. This study highlights the importance to consider multiple factors when assessing cognition in the oldest-old.

Background and ObjectivesTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid–positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.MethodsIn this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).ResultsWe included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = −0.18 to −0.11, false discovery rate [FDR]–adjustedp< 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = −0.32 to 0.36, all FDR-adjustedp> 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = −0.13 to 0.44, all FDR-adjustedp> 0.05).DiscussionNPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.

Cortical accumulation of amyloid beta is one of the first events of Alzheimer’s disease pathophysiology, and has been suggested to follow a consistent spatiotemporal ordering, starting in the posterior cingulate cortex, precuneus and medio-orbitofrontal cortex. These regions overlap with those of the default mode network, a brain network also involved in memory functions. Aberrant default mode network functional connectivity and higher network sparsity have been reported in prodromal and clinical Alzheimer’s disease. We investigated the association between amyloid burden and default mode network connectivity in the preclinical stage of Alzheimer’s disease and its association with longitudinal memory decline. We included 173 participants, in which amyloid burden was assessed both in CSF by the amyloid beta 42/40 ratio, capturing the soluble part of amyloid pathology, and in dynamic PET scans calculating the non-displaceable binding potential in early-stage regions. The default mode network was identified with resting-state functional MRI. Then, we calculated functional connectivity in the default mode network, derived from independent component analysis, and eigenvector centrality, a graph measure recursively defining important nodes on the base of their connection with other important nodes. Memory was tested at baseline, 2- and 4-year follow-up. We demonstrated that higher amyloid burden as measured by both CSF amyloid beta 42/40 ratio and non-displaceable binding potential in the posterior cingulate cortex was associated with lower functional connectivity in the default mode network. The association between amyloid burden (CSF and non-displaceable binding potential in the posterior cingulate cortex) and aberrant default mode network connectivity was confirmed at the voxel level with both functional connectivity and eigenvector centrality measures, and it was driven by voxel clusters localized in the precuneus, cingulate, angular and left middle temporal gyri. Moreover, we demonstrated that functional connectivity in the default mode network predicts longitudinal memory decline synergistically with regional amyloid burden, as measured by non-displaceable binding potential in the posterior cingulate cortex. Taken together, these results suggest that early amyloid beta deposition is associated with aberrant default mode network connectivity in cognitively healthy individuals and that default mode network connectivity markers can be used to identify subjects at risk of memory decline., Ingala et al. have investigated a cognitively unimpaired older population, finding that early-stage amyloid-β accumulation is associated with aberrant default mode network connectivity and consecutive memory decline. The markers reported in this study could support the diagnostic and prognostic assessment of individuals in the earliest stages of Alzheimer’s Disease., Graphical Abstract Graphical Abstract

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PurposeSemi-quantitative PET measures can be affected by changes in blood flow, whereas quantitative measures are not. The aim of the study was to compare semi-quantitative(SUVr) and quantitative(R1, BPND) parameters of longitudinal tau PET scans with [18F]flortaucipir, with respect to changes in blood flow.MethodsSubjects with subjective cognitive decline(SCD; n=38) and Alzheimer’s disease(AD) patients(n=24) underwent baseline(BL) and 2-year follow-up(FU) dynamic [18F]flortaucipir PET scans. BPND and R1 were estimated using RPM and SUVr(80-100min) was calculated (cerebellar gray as reference). For each region-of-interest ((trans)entorhinal, limbic and neocortical) and parameter, %change was calculated. Regional SUVrs were compared to corresponding DVR (= BPND+1) using paired T-tests. Additionally, simulations were performed to model effects of flow changes on BPND and SUVr in different binding categories. Thereafter, %bias for SUVr with respect to underlying binding and flow were evaluated.ResultsIn SCD, there was a difference between %change in the (trans)entorhinal ROI (DVR 2.56% vs SUVr 1.85%) only. In AD, a difference was found in the limbic ROI (DVR 6.61% vs SUVr 7.52%) only. R1 changes were small(+0.7% in SCD and -1.6% in AD). Simulations illustrated with increasing flow a decreased %bias for SUVr in low binding conditions, whereas a slightly increased bias was observed in high binding conditions.ConclusionSUVr provided an accurate estimate of specific binding for [18F]flortaucipir over a two-year follow-up. However, simulations showed that flow changes can affect [18F]flortaucipir SUVr, hence DVR/BPND should be preferred in more advanced disease stages and/or conditions that could induce significant flow changes like pharmacotherapeutic interventions.

Purpose The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (VT) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to VT, as a verification of the previously validated grey matter cerebellum reference region for [18F]flortaucipir and [18F]florbetapir PET imaging in Alzheimer’s disease (AD) patients and controls. Procedures Dynamic 130-min [18F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [18F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional VT’s were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUVBW), lean body mass (SUL), and body surface area (SUVBSA) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BPND) on the SUVs. Results A low SUV corresponded well with a low VT for both [18F]flortaucipir and [18F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding. Conclusions In situations where dynamic scanning and arterial sampling is not possible, a low SUV(80–100 min) for [18F]flortaucipir and a low SUV(50–70 min) for [18F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region.

Optimal pharmacokinetic models for quantifying amyloid beta (Aβ) burden using both [18F]flutemetamol and [18F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [18F]flutemetamol and [18F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [18F]flutemetamol (N=24) or [18F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90–110min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aβ-positive vs Aβ-negative scans ([18F]flutemetamol: range AUC=0.96–0.97 [18F]florbetaben: range AUC=0.83–0.85). Outcome parameters of most methods were highly correlated with the reference method (R2≥0.87), while lowest correlation were observed for MRTM2 (R2=0.71–0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression.

Accumulation of amyloid beta can be visualized using [18F]florbetapir positron emission tomography. The aim of this study was to identify the optimal model for quantifying [18F]florbetapir uptake and to assess test–retest reliability of corresponding outcome measures. Eight Alzheimer’s disease patients (age: 67 ± 6 years, Mini-Mental State Examination (MMSE): 23 ± 3) and eight controls (age: 63 ± 4 years, MMSE: 30 ± 0) were included. Ninety-minute dynamic positron emission tomography scans, together with arterial blood sampling, were acquired immediately following a bolus injection of 294 ± 32 MBq [18F]florbetapir. Several plasma input models and the simplified reference tissue model (SRTM) were evaluated. The Akaike information criterion was used to identify the preferred kinetic model. Compared to controls, Alzheimer’s disease patients had lower MMSE scores and evidence for cortical Aβ pathology. A reversible two-tissue compartment model with fitted blood volume fraction (2T4k_VB) was the preferred model for describing [18F]florbetapir kinetics. SRTM-derived non-displaceable binding potential (BPND) correlated well (r2 = 0.83, slope = 0.86) with plasma input-derived distribution volume ratio. Test–retest reliability for plasma input-derived distribution volume ratio, SRTM-derived BPND and SUVr(50–70) were r = 0.88, r = 0.91 and r = 0.86, respectively. In vivo kinetics of [18F]florbetapir could best be described by a reversible two-tissue compartmental model and [18F]florbetapir BPND can be reliably estimated using an SRTM.

ObjectiveTo apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features.MethodsWe included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time.ResultsThe proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A−T−N− (from 48% to 19% and 6%). Compared to A−T−N−, patients with the Alzheimer disease profiles (A+T+N− and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A−T−N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A−T−N−. A linear mixed model showed faster decline on MMSE over time in A+T+N− and A+T+N+ (p = 0.059 and p < 0.001 vs A−T−N−), attributable mainly to patients without dementia.ConclusionsThe ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.

Objective To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β‐amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch‐type hereditary cerebral amyloid angiopathy (D‐CAA) mutation. Methods PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB‐PET in 19 D‐CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M−). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M−). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M− participants who underwent lumbar puncture and compared the findings to PiB‐PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. Results D‐CAA M+ showed greater age‐dependent FLR PiB retention (p

The prevalence of brain pathologies increases with age and cognitive and physical functions worsen over the lifetime. It is unclear whether these processes show a similar increase with age. We studied the association of markers for brain pathology cognitive and physical functions with age in 288 cognitively normal individuals aged 60–102 years selected from the cross-sectional EMIF-AD PreclinAD and 90+ Study at the Amsterdam UMC. An abnormal score was consistent with a score below the 5th percentile in the 60- to 70-year-old individuals. Prevalence of abnormal scores was estimated using Generalized Estimating Equations (GEE) models. The prevalence of abnormal handgrip strength, the Digit Symbol Substitution Test, and hippocampal volume showed the fastest increase with age and abnormal MMSE score, muscle mass, and amyloid aggregation the lowest. The increase in prevalence of abnormal markers was partly dependent on sex, level of education, and amyloid aggregation. We did not find a consistent pattern in which markers of brain pathology cognitive and physical processes became abnormal with age.

Background/aimsAs a protrusion from the brain, the retina might reflect the status of the brain. Previous studies showed a decrease in vessel density and foveal avascular zone (FAZ) enlargement on optical coherence tomography angiography (OCTA) in individuals suffering from Alzheimer’s disease (AD). This study aims to assess whether such changes are already present in preclinical stages of AD, in a population of monozygotic (MZ) twins.Methods124 cognitively healthy individuals (MZ twins, ages 60–93 years) underwent [18F]flutemetamol amyloid positron emission tomography (PET) scanning and OCTA. PET scans were visually rated for cortical amyloid-beta (Aβ) positivity. Parametric global cortical non-displaceable binding potential (BPND) was used as a continuous measure for Aβ aggregation. FAZ size and vessel densities for the inner and outer ring of the macular ETDRS grid and in a 3–6 mm ring around the optic nerve head (ONH) were measured.OCTA measures were associated with visual Aβ score,BPNDand amyloid load estimated by twin concordance on visual Aβ score. Twin correlations were estimated as a measure of maximum heritability of OCTA measures.Results13 of 124 participants were Aβ+. Aβ+ individuals had significantly higher vessel density than Aβ– individuals in all regions but did not differ in FAZ size. Twin analyses showed a positive association between and vessel densities in all regions.BPNDtended to be associated with higher vessel density in the inner ring. Twin correlations were moderate/high for all OCTA parameters except vessel density around the ONH, which correlated weakly.ConclusionRetinal vessel density was higher in individuals with preclinical AD.

Introduction The retina is a potential source of noninvasive vascular biomarkers for Alzheimer's disease (AD). We assessed retinal microvasculature in well-characterized AD cases, taking ophthalmological confounders into account. Methods We included 48 amyloid-positive AD patients and 38 amyloid-negative cognitively normal control subjects. All participants underwent ophthalmological screening to exclude interfering ocular disease. Using a multimodal approach, we measured retinal vascular parameters, choroidal thickness, macular vascular density, and foveal avascular zone size. Results We found no disease effects on retinal vascular measures (all β′s .2), adjusted for confounders. Venular tortuosity was inversely associated with Fazekas score in control subjects (β −0.56, P, Highlights • Retinal vascular measures did not differ between patients with Alzheimer's disease and control participants. • Venular tortuosity was inversely associated with Fazekas score in control subjects. • Macular vessel density was inversely associated with Fazekas score in AD cases.

Amyloid pathology in cognitively normal older adults has been associated with low memory performance and cognitive complaints, but findings are conflicting. Using a monozygotic twin design, we further explored this relation. We investigated 199 cognitively normal older adults (96 twin pairs) and assessed cognitive performance, cognitive complaints, and amyloid pathology on positron emission tomography and in the cerebrospinal fluid (CSF). Participants were on average 70.5 (SD = 7.6) years and 114 (57%) were female. Amyloid-positron emission tomography abnormality on visual read and lower CSFamyloid-beta 1-42/1-40 ratio were associated with lower Rey visuospatial memory performance (respectively, beta = -0.39 [SE = 0.17], p = 0.02 and beta = 0.15 [SE = 0.07], p = 0.04). Twin analyses showed that CSF amyloid-beta 1-42/1-40 ratio in one twin of a pair could predict visuospatial memory performance in the cotwin (r = 0.20 [SE = 0.10], p = 0.04). Monozygotic twin discordance analyses further showed a probable effect of disease staging on face-name associative memory performance. Our results suggest amyloid aggregation to be associated with lower visuospatial and face-name-associated memory performance in cognitively normal older adults, supporting the view that amyloid pathology leads to memory dysfunction in very early stages of the disease. (C) 2019 The Authors. Published by Elsevier Inc.

PURPOSE: There is urgent need for non-invasive diagnostic biomarkers in the preclinical phase of Alzheimer's Disease (AD). Several studies suggest that retinal thickness is reduced in AD. Here, we aim to test the diagnostic value of retinal thickness in preclinical AD, as defined by cognitively normal individuals with amyloid pathology on PET.METHODS: One hundred and sixty five cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the European Medical Information Framework for Alzheimer's Disease PreclinAD study. Participants underwent [18 F] flutemetamol PET that was visually rated for presence or absence of cortical amyloid beta (Aβ). Binding potential (BPND ) was calculated as continuous measure for Aβ. Spectral Domain OCT was used to asses total and individual inner retinal layer thickness in the macular region (ETDRS circles) as well as peripapillary retinal nerve fibre layer (pRNFL) thickness. Differences between Aβ+ and Aβ- individuals and associations between BPND and retinal thickness were analyzed.RESULTS: No differences were found in retinal layer thickness in the macula or pRNFL between Aβ+ and Aβ- individuals. A positive associations between BPND and macular total retinal thickness was observed in the inner ring (p = 0.018), but this was not statistically significant after correction for multiple testing (p = 0.144). Brain/eye parameters had moderate to high intra-twin correlations (p < 0.001) except visual rating score of Aβ, which did not correlate (r = 0.21, p = 0.068).CONCLUSION: Variation in retinal thickness likely reflects genetic differences between individuals, but cannot discriminate between healthy and preclinical AD cases, making its use as biomarker in these early stages limited.

Our objective was to determine the optimal approach for assessing amyloid disease in a cognitively normal elderly population.Methods:Dynamic18F-flutemetamol PET scans were acquired using a coffee-break protocol (a 0- to 30-min scan and a 90- to 110-min scan) on 190 cognitively normal elderly individuals (mean age, 70.4 y; 60% female). Parametric images were generated from SUV ratio (SUVr) and nondisplaceable binding potential (BPND) methods, with cerebellar gray matter as a reference region, and were visually assessed by 3 trained readers. Interreader agreement was calculated using κ-statistics, and semiquantitative values were obtained. Global cutoffs were calculated for both SUVr and BPNDusing a receiver-operating-characteristic analysis and the Youden index. Visual assessment was related to semiquantitative classifications.Results:Interreader agreement in visual assessment was moderate for SUVr (κ = 0.57) and good for BPNDimages (κ = 0.77). There was discordance between readers for 35 cases (18%) using SUVr and for 15 cases (8%) using BPND, with 9 overlapping cases. For the total cohort, the mean (±SD) SUVr and BPNDwere 1.33 (±0.21) and 0.16 (±0.12), respectively. Most of the 35 cases (91%) for which SUVr image assessment was discordant between readers were classified as negative based on semiquantitative measurements.Conclusion:The use of parametric BPNDimages for visual assessment of18F-flutemetamol in a population with low amyloid burden improves interreader agreement. Implementing semiquantification in addition to visual assessment of SUVr images can reduce false-positive classification in this population.

Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [ 18 ]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer's disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer's Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between [ 18 ]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [ 18 ]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods.

Self-perceived word-finding difficulties are common in aging individuals as well as in Alzheimer's Disease (AD). Language and speech deficits are difficult to objectify with neuropsychological assessments. We therefore aimed to investigate whether amyloid, an early AD pathological hallmark, is associated with speech-derived semantic complexity. We included 63 individuals with subjective cognitive decline (age 64 ± 8, MMSE 29 ± 1), with amyloid status (positron emission tomography [PET] scans n = 59, or Aβ1-42 cerebrospinal fluid [CSF] n = 4). Spontaneous speech was recorded using three open-ended tasks (description of cookie theft picture, abstract painting and a regular Sunday), transcribed verbatim and subsequently, linguistic parameters were extracted using T-scan computational software, including specific words (content words, frequent, concrete and abstract nouns, and fillers), lexical complexity (lemma frequency, Type-Token-Ratio) and syntactic complexity (Developmental Level scale). Nineteen individuals (30%) had high levels of amyloid burden, and there were no differences between groups on conventional neuropsychological tests. Using multinomial regression with linguistic parameters (in tertiles), we found that high amyloid burden is associated with fewer concrete nouns (ORmiddle (95%CI): 7.6 (1.4–41.2), ORlowest: 6.7 (1.2–37.1)) and content words (ORlowest: 6.3 (1.0–38.1). In addition, we found an interaction for education between high amyloid burden and more abstract nouns. In conclusion, high amyloid burden was modestly associated with fewer specific words, but not with syntactic complexity, lexical complexity or conventional neuropsychological tests, suggesting that subtle spontaneous speech deficits might occur in preclinical AD.

Background and ObjectivesMultiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD).MethodsWe included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). We used the following N biomarkers: CSF total tau (t-tau), medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL), and serum glial fibrillary acidic protein (GFAP). We determined correlations between biomarkers. We assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression) and Mini-Mental State Examination (MMSE) over time (linear mixed models). Models included age, sex, CSF β-amyloid (Aβ) (A), and CSF p-tau (T) as covariates, in addition to the N biomarker.ResultWe included 401 individuals (61±9 years, 42% female, MMSE 28 ± 2, vascular comorbidities 8%–19%). N biomarkers were modestly to moderately correlated (range r −0.28 – 0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL, and GFAP added predictive value beyond Aβ and p-tau (hazard ratio 1.52 [95% CI 1.11–2.09]; 1.51 [1.05–2.17]; 1.50 [1.04–2.15]). T-tau, HV, and GFAP individually predicted MMSE slope (range β −0.17 to −0.11, p < 0.05), but only HV remained associated beyond Aβ and p-tau (β −0.13 [SE 0.04]; p < 0.05).DiscussionIn cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as a measure for N. HV, NfL, and GFAP predicted clinical progression beyond A and T. Our results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T.Classification of EvidenceThis study provides Class II evidence that HV, NfL, and GFAP predicted clinical progression beyond A and T in individuals with SCD.