Longitudinal associations of serum biomarkers with early cognitive, amyloid and grey matter changes.

Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-ß (Aß) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aß1-42/Aß1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aß-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aß-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aß1-42/Aß1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (ßGFAP×Time = -0.021, PFDR = 0.007 and ßNfL×Time = -0.031, PFDR = 0.002) and language (ßGFAP×Time = -0.021, PFDR = 0.002 and ßNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aß1-42/Aß1-40 equally but independently predicted memory decline (ßAß1-42/Aß1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aß1-42/Aß1-40 predicted Aß accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aß1-42/Aß1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aß1-42/Aß1-40 decreased only in Aß-PET-negative elderly. NfL increases associated with declining memory (ßNfLchange×Time = -0.030, PFDR = 0.006) and language (ßNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aß1-42/Aß1-40 decreases associated with declining language function (ßAß1-42/Aß1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aß accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aß accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aß1-42/Aß1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aß-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aß-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aß1-42/Aß1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.

Classification of 18F-Flutemetamol scans in cognitively normal older adults using machine learning trained with neuropathology as ground truth.

PURPOSE: End-of-life studies have validated the binary visual reads of 18F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults. METHODS: We applied SVM with a linear kernel to an 18F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers' diagnostic performance in the asymptomatic Alzheimer's disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK. RESULTS: The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was -0.66 for the classifier trained with neuritic amyloid plaque density, and -0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48-51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%), which closely matched the CL threshold for discriminating phases 0-2 from 3-5 based on the end-of-life dataset and the neuropathological ground truth. DISCUSSION: Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights.

Changes in the language system as amyloid-ß accumulates.

Language dysfunction is common in Alzheimer's disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer's disease. Here we examined in 35 cognitively intact older adults (age range 52-78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a 5-6-year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex. In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuo-perceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxel-wise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in functional MRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer's disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer's disease.

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults.

The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross-sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18 F]-flutemetamol amyloid positron emission tomography, and T1 -weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t-tau, α-synuclein, p-tau181 , neurogranin, BACE1, visinin-like protein 1, chitinase-3-like protein 1 (YKL-40), Aß1-40 and Aß1-38 . Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin-like protein 1, neurogranin, BACE1, Aß1-40 , Aß1-38, and YKL-40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL-40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre-registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Cross-modal representation of spoken and written word meaning in left pars triangularis.

The correspondence in meaning extracted from written versus spoken input remains to be fully understood neurobiologically. Here, in a total of 38 subjects, the functional anatomy of cross-modal semantic similarity for concrete words was determined based on a dual criterion: First, a voxelwise univariate analysis had to show significant activation during a semantic task (property verification) performed with written and spoken concrete words compared to the perceptually matched control condition. Second, in an independent dataset, in these clusters, the similarity in fMRI response pattern to two distinct entities, one presented as a written and the other as a spoken word, had to correlate with the similarity in meaning between these entities. The left ventral occipitotemporal transition zone and ventromedial temporal cortex, retrosplenial cortex, pars orbitalis bilaterally, and the left pars triangularis were all activated in the univariate contrast. Only the left pars triangularis showed a cross-modal semantic similarity effect. There was no effect of phonological nor orthographic similarity in this region. The cross-modal semantic similarity effect was confirmed by a secondary analysis in the cytoarchitectonically defined BA45. A semantic similarity effect was also present in the ventral occipital regions but only within the visual modality, and in the anterior superior temporal cortex only within the auditory modality. This study provides direct evidence for the coding of word meaning in BA45 and positions its contribution to semantic processing at the confluence of input-modality specific pathways that code for meaning within the respective input modalities.

Functional Changes in the Language Network in Response to Increased Amyloid ß Deposition in Cognitively Intact Older Adults.

Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden.

Amyloid imaging in cognitively normal older adults: comparison between (18)F-flutemetamol and (11)C-Pittsburgh compound B.

PURPOSE: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). METHODS: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. RESULTS: Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. CONCLUSION: For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.

The interest of amyloid PET imaging in the diagnosis of Alzheimer's disease.

PURPOSE OF REVIEW: This review evaluates the potential clinical utility of amyloid imaging. RECENT FINDINGS: Amyloid PET is a valid in-vivo marker of neuritic plaque load and correlates with amyloid plaque surface area. Abundant diffuse plaques, however, with scant neuritic plaques can also give rise to a positive scan, most often reported in association with Lewy body disease. Specificity of amyloid PET for discriminating Alzheimer's disease from healthy controls is higher than that of structural MRI. Sensitivity for discriminating Alzheimer's disease from healthy controls or from frontotemporal lobar degeneration is also higher than that of fluorodeoxyglucose-PET, with higher interreader reliability. Within a same center there is high concordance between dichotomization of cases based on amyloid PET versus cerebrospinal fluid Aß42. In a tentative algorithm, we restrict clinical-diagnostic use to dementia with age of onset before 60 years, primary progressive aphasia and corticobasal syndrome, cases with objective cognitive deficits that could be due to a neurodegenerative cause but also have significant cerebrovascular or psychiatric comorbidity, and rapidly progressive dementia. SUMMARY: Empirical studies that evaluate how amyloid PET can change clinical-diagnostic thinking are starting to emerge. Key questions to be resolved are its role compared with cerebrospinal fluid markers and its impact on patient outcome.

Longitudinal changes in 18F-Flutemetamol amyloid load in cognitively intact APOE4 carriers versus noncarriers: Methodological considerations.

PURPOSE: Measuring longitudinal changes in amyloid load in the asymptomatic stage of Alzheimer's disease is of high relevance for clinical research and progress towards more efficacious, timely treatments. Apolipoprotein E ε4 (APOE4) has a well-established effect on the rate of amyloid accumulation. Here we investigated which region of interest and which reference region perform best at detecting the effect of APOE4 on longitudinal amyloid load in individuals participating in the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK). METHODS: Ninety cognitively intact F-PACK participants (baseline age: 68 (52-80) years, 46 males, 42 APOE4 carriers) received structural MRI and 18F-Flutemetamol PET scans at baseline and follow-up (6.2 (3.4-10.9) year interval). Standardised uptake value ratios (SUVRs) and Centiloids (CLs) were calculated in a composite cortical volume of interest (SUVRcomp/CL) and in the precuneus (SUVRprec), and amyloid rate of change derived: (follow-up amyloid load - baseline amyloid load) / time interval (years). Four reference regions were used to derive amyloid load: whole cerebellum, cerebellar grey matter, eroded subcortical white matter, and pons. RESULTS: When using whole cerebellum or cerebellar grey matter as reference region, APOE4 carriers had a significantly higher SUVRcomp amyloid rate of change than non-carriers (pcorr = 0.004, t = 3.40 (CI 0.005-0.018); pcorr = 0.036, t = 2.66 (CI 0.003-0.018), respectively). Significance was not observed for eroded subcortical white matter or pons (pcorr = 0.144, t = 2.13 (CI 0.0003-0.008); pcorr = 0.116, t = 2.22 (CI 0.005-0.010), respectively). When using CLs as the amyloid measurement, and whole cerebellum, APOE4 carriers had a higher amyloid rate of change than non-carriers (pcorr = 0.012, t = 3.05 (CI 0.499-2.359)). Significance was not observed for the other reference regions. No significance was observed with any of the reference regions and amyloid rate of change in the precuneus (SUVRprec). CONCLUSION: In this cognitively intact cohort, a composite neocortical volume of interest together with whole cerebellum or cerebellar grey matter as reference region are the methods of choice for detecting APOE4-dependent differences in amyloid rate of change.

Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults.

BACKGROUND: Gene expression is dysregulated in Alzheimer's disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. METHODS: RNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56-80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4-8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation. RESULTS: There were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r2 = - 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r2 = - 0.27, p = 0.035) and one upregulated (r2 = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing. CONCLUSIONS: We show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development.

Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET.

Background: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Chronometry of word and picture identification: common and modality-specific effects.

Based on a previous fMRI connectivity analysis, we previously proposed that long-distance connections between left inferior frontal sulcus and left occipitotemporal sulcus mediate access to visual short-term memory both for written words and pictures enhancing conscious perception and successful encoding in an amodal manner. Using a 64-channel event-related potential electrode system in 19 young cognitively intact volunteers, we determined the chronometry of common and input-modality specific effects of word and picture identification and subsequent memory retrieval. Stimulus durations were calibrated per subject, modality and run so as to reach a 50% positive identification report. The earliest main effect of a positive identification report occurred between 180 and 200 ms, was common for both input-modalities, had a positive polarity and was located at around CPz. This effect was followed between 270 and 450 ms by additional common positive-polarity effects at centrofrontal electrode sites and by common negative effects at P7/P8, TP7/TP8 and T8. Each of the later effects was closely associated not only with identification but also with subsequent memory retrieval. The earliest input-modality specific effect of conscious identification that we detected occurred from 280 till 440 ms at P8. Our findings are in line with a model where the initial stages of perceptual identification and visual short-term memory access rely on long-distance connections that are shared between written words and pictures.

Evaluation of 18F-flutemetamol amyloid PET image analysis parameters on the effect of verubecestat on brain amlyoid load in Alzheimer's disease.

PURPOSE: The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by 18F-flutemetamol positron emission tomography (PET) composite cortical standard uptake value ratio (SUVr) in patients with mild-to-moderate Alzheimer's disease (AD) in a substudy of the EPOCH trial. Here, we report on additional analyses relevant to the EPOCH PET data, to help inform on the use of PET for assessing amlyloid load in AD clinical trials. PROCEDURES: The analyses addressed (1) identification of an optimal 18F-flutemetamol reference region, (2) determination of the threshold to characterize the magnitude of the longitudinal change, and (3) the impact of partial volume correction (PVC). Pons and subcortical white matter were evaluated as reference regions. The SUVr cutoffs and final reference region choice were determined using 162 18F-flutemetamol PET scans from the AIBL dataset. 18F-flutemetamol SUVrs were computed at baseline and at Week 78 in EPOCH participants who received verubecestat 12 mg (n = 14), 40 mg (n = 20), or placebo (n = 20). Drug effects on amyloid load were computed using either Meltzer (MZ), or symmetric geometric transfer matrix (SGTM) PVC and compared to uncorrected data. RESULTS: The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r2 = 0.94) and SGTM PVC (r2 = 0.92) baseline SUVr values, and PVC did not provide improvement for evaluating treatment effects on amyloid load at Week 78. No change from baseline was observed in the placebo group at Week 78, whereas a 0.02 and a 0.04 decrease in SUVr were observed in the 12 mg and 40 mg arms, with the latter representing a 22% reduction in the amyloid load above the detection threshold. CONCLUSIONS: Treatment-related 18F-flutemetamol longitudinal changes in AD clinical trials can be quantified using a subcortical white matter reference region without PVC. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01739348.

Association of Alzheimer's disease polygenic risk scores with amyloid accumulation in cognitively intact older adults.

BACKGROUND: Early detection of individuals at risk for Alzheimer's disease (AD) is highly important. Amyloid accumulation is an early pathological AD event, but the genetic association with known AD risk variants beyond the APOE4 effect is largely unknown. We investigated the association between different AD polygenic risk scores (PRS) and amyloid accumulation in the Flemish Prevent AD Cohort KU Leuven (F-PACK). METHODS: We calculated PRS with and without the APOE region in 90 cognitively healthy F-PACK participants (baseline age 67.8 (52-80) years, 41 APOE4 carriers), with baseline and follow-up amyloid-PET (time interval 6.1 (3.4-10.9) years). Individuals were genotyped using Illumina GSA and imputed. PRS were calculated using three p-value thresholds (pT) for variant inclusion: 5 × 10-8, 1 × 10-5, and 0.1, based on the stage 1 summary statistics from Kunkle et al. (Nat Genet 51:414-30, 2019). Linear regression models determined if these PRS predicted amyloid accumulation. RESULTS: A score based on PRS excluding the APOE region at pT = 5 × 10-8 plus the weighted sum of the two major APOE variants (rs429358 and rs7412) was significantly associated with amyloid accumulation (p = 0.0126). The two major APOE variants were also significantly associated with amyloid accumulation (p = 0.0496). The other PRS were not significant. CONCLUSIONS: Specific PRS are associated with amyloid accumulation in the asymptomatic phase of AD.

Baseline cognition is the best predictor of 4-year cognitive change in cognitively intact older adults.

BACKGROUND: We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course. METHODS: One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52-80 years, 81 women) belonging to the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and 18F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change. RESULTS: A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline. CONCLUSION: In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.

Electroconvulsive therapy response in late-life depression unaffected by age-related brain changes.

BACKGROUND: Gray matter volume decrease, white matter vascular pathology and amyloid accumulation are age-related brain changes that have been related to the pathogenesis of late life depression (LLD). Furthermore, lower hippocampal volume and more white matter hyperintensities (WMH) may contribute to poor response to electroconvulsive therapy (ECT) in severely depressed older adults. We hypothesized that the accumulation of age-related brain changes negatively affects outcome following ECT in LLD. METHODS: 34 elderly patients with severe LLD were treated twice weekly with ECT until remission. All had both 3T structural magnetic resonance imaging (MRI) and ß-amyloid positron emission tomography (PET) imaging using 18F-flutemetamol at baseline. MADRS and MMSE were obtained weekly which included 1 week prior to ECT (T0), after the sixth ECT (T1), and one week (T2) after the last ECT as well as at four weeks (T3) and 6 months (T4) after the last ECT. We conducted a multiple logistic regression analysis and a survival analysis with neuroimaging measures as predictors, and response, remission and relapse as outcome variable. RESULTS: We did not find any association between baseline hippocampal volume, white matter hyperintensity volume and total amyloid load and response or remission at 1 and 4 weeks post ECT, nor with relapse at week 4. LIMITATIONS: The present exploratory study was conducted at a single center academic hospital, the sample size was small, the focus was on hippocampal volume and the predictive effect of structural and molecular changes associated with aging were used. CONCLUSIONS: Our study shows no evidence of relationship between response to ECT and age-related structural or molecular brain changes, implying that ECT can be applied effectively in depressed patients irrespective of accumulating age-related brain changes.

Serum neurofilament heavy chains as early marker of motor neuron degeneration.

OBJECTIVE: To determine whether serum phosphorylated neurofilament heavy chain (pNfH) levels are elevated before patients were diagnosed with sporadic or familial ALS, and what the prognostic value of these prediagnostic pNfH levels is. METHODS: pNfH was measured via ELISA in leftovers of serum drawn for routine purposes before the time of diagnosis. These prediagnostic samples were retrieved from the biobank of the University Hospitals Leuven for 95 patients who in follow-up received a diagnosis of ALS. Additionally, 35 patients with mild cognitive impairment (MCI) and 85 healthy controls (HC) were included in this retrospective study. RESULTS: The median disease duration (range) from onset to prediagnostic sampling and from onset to diagnosis was 6.5 (-71.9-36.1) and 9.9 (2.0-40.7) months, respectively. Fifty-eight percent of the prediagnostic samples had serum pNfH levels above the 95th percentile of pNfH levels measured in HC. Serum pNfH levels (median (range)) were elevated up to 18 months before the diagnosis of ALS (91 pg/mL (6-342 pg/mL)) in comparison with HC (30 pg/mL (6-146 pg/mL); P = 0.05), and increased during the prediagnostic stage, which was not observed in patients with MCI. Furthermore, prediagnostic pNfH levels were a univariate predictor of survival in ALS (hazard ratio (95% CI): 2.16 (1.20-3.87); P = 0.01). INTERPRETATION: Our findings demonstrate that serum pNfH is elevated well before the time of diagnosis in mainly sporadic ALS patients. These results encourage to prospectively explore if pNfH has an added value to shorten the diagnostic delay in ALS.

Corpus callosum macro and microstructure in late-life depression.

BACKGROUND: Differences in corpus callosum (CC) morphology and microstructure have been implicated in late-life depression and may distinguish between late and early-onset forms of the illness. However, a multimodal approach using complementary imaging techniques is required to disentangle microstructural alterations from macrostructural partial volume effects. METHODS: 107 older adults were assessed: 55 currently-depressed patients without dementia and 52 controls without cognitive impairment. We investigated group differences and clinical associations in 7 sub-regions of the mid-sagittal corpus callosum using T1 anatomical data, white matter hyperintensity (WMH) quantification and two different diffusion MRI (dMRI) models (multi-tissue constrained spherical deconvolution, yielding apparent fibre density, AFD; and diffusion tensor imaging, yielding fractional anisotropy, FA and radial diffusivity, RD). RESULTS: Callosal AFD was lower in patients compared to controls. There were no group differences in CC thickness, surface area, FA, RD, nor whole brain or WMH volume. Late-onset of depression was associated with lower FA, higher RD and lower AFD. There were no associations between any imaging measures and psychotic features or depression severity as assessed by the geriatric depression scale. WMH volume was associated with lower FA and AFD, and higher RD in patients. LIMITATIONS: Patients were predominantly treatment-resistant. Measurements were limited to the mid-sagittal CC. dMRI analysis was performed on a smaller cohort, n=77. AFD was derived from low b-value data. CONCLUSIONS: Callosal structure is largely preserved in LLD. WMH burden may impact on CC microstructure in late-onset depression suggesting vascular pathology has additional deleterious effects in these patients.