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Purpose: We aim to report the quality of accuracy studies investigating the utility of [18F]fluorodeoxyglucose (FDG)-PET in supporting the diagnosis of prodromal Alzheimer’s Disease (AD), frontotemporal lobar degeneration (FTLD) and prodromal dementia with Lewy bodies (DLB) in mild cognitive impairment (MCI) subjects, and the corresponding recommendations made by a panel of experts. Methods: Seven panellist, four from the European Association of Nuclear Medicine, and three from the European Academy of Neurology, produced recommendations taking into consideration the incremental value of FDG-PET, as added on clinical-neuropsychological examination, to ascertain the aetiology of MCI (AD, FTLD or DLB). A literature search using harmonized population, intervention, comparison, and outcome (PICO) strings was performed, and an evidence assessment consistent with the European Federation of Neurological Societies guidance was provided. The consensual recommendation was achieved based on Delphi rounds. Results: Fifty-four papers reported the comparison of interest. The selected papers allowed the identification of FDG patterns that characterized MCI due to AD, FTLD and DLB. While clinical outcome studies supporting the diagnosis of MCI due to AD showed varying accuracies (ranging from 58 to 100%) and varying areas under the receiver-operator characteristic curves (0.66 to 0.97), no respective data were identified for MCI due to FTLD or for MCI due to DLB. However, the high negative predictive value of FDG-PET and the existence of different disease-specific patterns of hypometabolism support the consensus recommendations for the clinical use of this imaging technique in MCI subjects. Conclusions: FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD. Although promising also in detecting MCI due to FTLD and MCI due to DLB, more research is needed to ultimately judge the clinical utility of FDG-PET in these entities.

Purpose: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer’s disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) ε4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. Methods: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. Results: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE ε4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. Conclusion: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE ε4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications.

Purpose: A joint effort of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) aims at clinical guidance for the use of FDG-PET in neurodegenerative diseases. This paper addresses the diagnostic utility of FDG-PET over clinical/neuropsychological assessment in the differentiation of the three forms of primary progressive aphasia (PPA). Methods: Seven panelists were appointed by the EANM and EAN and a literature search was performed by using harmonized PICO (Population, Intervention, Comparison, Outcome) question keywords. The studies were screened for eligibility, and data extracted to assess their methodological quality. Critical outcomes were accuracy indices in differentiating different PPA clinical forms. Subsequently Delphi rounds were held with the extracted data and quality assessment to reach a consensus based on both literature and expert opinion. Results: Critical outcomes for this PICO were available in four of the examined papers. The level of formal evidence supporting clinical utility of FDG-PET in differentiating among PPA variants was considered as poor. However, the consensual recommendation was defined on Delphi round I, with six out of seven panelists supporting clinical use. Conclusions: Quantitative evidence demonstrating utility or lack thereof is still missing. Panelists decided consistently to provide interim support for clinical use based on the fact that a typical atrophy or metabolic pattern is needed for PPA according to the diagnostic criteria, and the synaptic failure detected by FDG-PET is an earlier phenomenon than atrophy. Also, a normal FDG-PET points to a non-neurodegenerative cause.

Introduction The retina may reflect Alzheimer's disease (AD) neuropathological changes and is easily visualized with optical coherence tomography (OCT). Retinal thickness decrease has been correlated to AD, however, without information on amyloid status. We correlated retinal (layer) thickness to AD biomarkers in amyloid-positive early-onset AD (EOAD) patients and amyloid-negative controls. Methods We measured macular thickness and peripapillary retinal nerve fiber layer thickness with OCT in 15 EOAD patients and 15 controls and correlated retinal thickness to visual rating scores for atrophy on magnetic resonance imaging. Results Total macular thickness correlated to parietal cortical atrophy in both groups (Spearman ρ −0.603, P = .001). Macular and peripapillary retinal nerve fiber layer thicknesses were not significantly decreased in EOAD compared to controls. Discussion Retinal thickness does not discriminate EOAD from controls but is correlated to parietal cortical atrophy in both groups. These findings may suggest reflection of cerebral cortical changes in the retina, independent of amyloid., Highlights • Retinal thickness correlates with parietal cortical atrophy in amyloid-positive early-onset Alzheimer's disease patients and amyloid-negative controls. • Macular and retinal nerve fiber layer thicknesses do not discriminate amyloid-positive early-onset AD patients from amyloid-negative controls. • Reflection of cerebral cortical changes may be present in the retina, independent of amyloid.

We aimed to investigate associations between regional cortical thickness and rate of decline over time in 4 cognitive domains in patients with subjective cognitive decline (SCD). We included 233 SCD patients with the total number of 654 neuropsychological assessments (median = 3, range = 2–8) and available baseline magnetic resonance imaging from the Amsterdam Dementia Cohort (125 males, age: 63 ± 9, Mini–Mental State Examination score: 28 ± 2). We assessed longitudinal cognitive functioning at baseline and follow-up in 4 cognitive domains (composite Z-scores): memory, attention, executive function, and language. Thickness (millimeter) was estimated using FreeSurfer for frontal, temporal, parietal, cingulate, and occipital cortices. We used linear mixed models to estimate effects of cortical thickness on cognitive performance (dependent variables). There were no associations between cortical thickness and baseline cognition, but a faster subsequent rate of memory loss was associated with thinner cortex of the frontal [β (SE) = 0.20 (0.07)], temporal [β (SE) = 0.18 (0.07)], and occipital [β (SE) = 0.22 (0.09)] cortices (all p < 0.05FDR). These findings illustrate that early cortical changes, particularly in the temporal cortex, herald incipient cognitive decline related to neurodegenerative diseases, most prominently Alzheimer's disease.

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder of the brain, clinically characterised by cognitive deficits that gradually worsen over time. There is, at present, no established cure, or disease-modifying treatments for AD. As life expectancy increases globally, the number of individuals suffering from the disease is projected to increase substantially. Cumulative evidence indicates that AD neuropathological process is initiated several years, if not decades, before clinical signs are evident in patients, and diagnosis made. While several imaging, cognitive, CSF and blood-based biomarkers have been proposed for the early detection of AD; their sensitivity and specificity in the symptomatic stages is highly variable and it is difficult to justify their use in even earlier, pre-clinical stages of the disease. Research has identified potentially measurable functional, structural, metabolic and vascular changes in the retina during early stages of AD. Retina offers a distinctively accessible insight into brain pathology and current and developing ophthalmic technologies have provided us with the possibility of detecting and characterising subtle, disease-related changes. Recent human and animal model studies have further provided mechanistic insights into the biochemical pathways that are altered in the retina in disease, including amyloid and tau deposition. This information coupled with advances in molecular imaging has allowed attempts to monitor biochemical changes and protein aggregation pathology in the retina in AD. This review summarises the existing knowledge that informs our understanding of the impact of AD on the retina and highlights some of the gaps that need to be addressed. Future research will integrate molecular imaging innovation with functional and structural changes to enhance our knowledge of the AD pathophysiological mechanisms and establish the utility of monitoring retinal changes as a potential biomarker for AD.

Introduction This study explores clinicians’ views on and experiences with when, how, and by whom decisions about diagnostic testing for Alzheimer's disease are made and how test results are discussed with patients. Methods Following a preparatory focus group with 13 neurologists and geriatricians, we disseminated an online questionnaire among 200 memory clinic clinicians. Results Respondents were 95 neurologists and geriatricians (response rate 47.5%). Clinicians (74%) indicated that decisions about testing are made before the first encounter, yet they favored a shared decision-making approach. Patient involvement seems limited to receiving information. Clinicians with less tolerance for uncertainty preferred a bigger say in decisions (P < .05). Clinicians indicated to always communicate the diagnosis (94%), results of different tests (88%–96%), and risk of developing dementia (66%). Discussion Clinicians favor patient involvement in deciding about diagnostic testing, but conversations about decisions and test results can be improved and supported.

Introduction The Alzheimer's biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI) Methods ABIDE is a 3-year project with a multifaceted design and is structured into interconnected substudies using both quantitative and qualitative research methods. Results Based on retrospective data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations. Discussion Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results.

Background Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. Methods In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

Introduction Retinal characteristics are increasingly recognized as biomarkers for neurodegenerative diseases. Retinal thickness measured by optical coherence tomography may reflect the presence of Alzheimer's disease (AD). We performed a meta-analysis on retinal thickness in AD and mild cognitive impairment (MCI) patients and healthy controls (HCs). Methods We selected 25 studies with measurements of retinal thickness including 887 AD patients, 216 MCI patients, and 864 HCs that measured retinal thickness. Outcomes were peripapillary retinal nerve fiber layer (RNFL) and macular thickness. The main outcome was the standardized mean differences (SMDs). We used STATA to perform the meta-analysis (StataCorp, Texas; version 14.0). Results Relative to HCs, AD and MCI patients had lower peripapillary RNFL (SMD 0.98 [CI −1.30, −0.66, P

Patients with dementia have a shorter life expectancy compared with the general population. Survival time after diagnosis varies greatly however, with reported median survival times between 3 and 12 years.1 2 This variation could be due to many factors, such as type of dementia, patient characteristics and change in management over time.3 4 We aimed to study median survival times after a dementia diagnosis in a memory clinic-based cohort across different types of dementia, mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Furthermore, we studied how age and sex influenced survival times. Finally, we studied whether median survival has changed over the past decades. From the Amsterdam Dementia Cohort,5 we included 4495 subjects with a baseline visit between 2000 and 2014 and a diagnosis of any type of dementia (n=2625), MCI (n=739) or SCD (n=1131) who served as controls. The group of patients with dementia included 1690 dementia due to Alzheimer’s disease (AD), 399 frontotemporal dementia (FTD), 165 vascular dementia (VaD) and 192 dementia with Lewy bodies (DLB). There were 179 with more rare causes of dementia, summarised as ‘other dementias’. The study was approved by the local Medical Ethical Committee. Information on mortality was obtained from the Dutch Municipal Register (accessed 14 September 2017). Survival duration was defined as years between date of baseline diagnosis and date of death or, when still alive, years between date of baseline diagnosis and 14 September 2017. We determined median survival times using Kaplan-Meier analyses, per diagnosis and stratified for age and sex. Furthermore, we assessed whether median survival in our cohort had changed over the past decades. Finally, for illustrative purposes, we compared median survival per decade for dementia due to AD and non-AD (pooling FTD, VaD, DLB and other …

Post-mortem in situ MRI has been used as an intermediate between brain histo(patho)logy and in vivo imaging. However, it is not known how comparable post-mortem in situ is to ante-mortem imaging. We report the unique situation of a patient with familial early-onset Alzheimer’s disease due to a PSEN1 mutation, who underwent ante-mortem brain MRI and post-mortem in situ imaging only 4 days apart. T1-weighted and diffusion MRI was performed at 3-Tesla at both time points. Visual atrophy rating scales, brain volume, cortical thickness and diffusion measures were derived from both scans and compared. Post-mortem visual atrophy scores decreased 0.5–1 point compared with ante-mortem, indicating an increase in brain volume. This was confirmed by quantitative analysis; showing a 27% decrease of ventricular and 7% increase of whole-brain volume. This increase was more pronounced in the cerebellum and supratentorial white matter than in grey matter. Furthermore, axial and radial diffusivity decreased up to 60% post-mortem whereas average fractional anisotropy of white matter increased approximately 10%. This unique case study shows that the process of dying affects several imaging markers. These changes need to be taken into account when interpreting post-mortem MRI to make inferences on the in vivo situation., Post-mortem brain imaging is used in many neurodegenerative disorders to validate imaging markers with immunohistopathology. This unique case study evaluates whether post-mortem brain imaging is a valid proxy for linking histopathology to the in vivo situation and demonstrates that MRI measurements significantly alter after death., Graphical Abstract Graphical Abstract

Background In vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10–20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories. Methods We included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer’s dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression. Results We found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = − 10.6, P Z = − 13.7, P Z = − 13.7, P β [SE] − 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (β − 0.75[0.08] patients (Pinteraction P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive. Conclusions Discordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.

Background Information given to patients and caregivers during the clinician-patient encounter varies considerably between memory clinic professionals. Patients and caregivers express a clear desire for more information. It is unclear what information patients and caregivers value most during the diagnostic process and whether this is concordant with professionals’ opinion. We aimed to identify a topic list on which health care professionals, patients, and caregivers agree that these should be discussed during diagnostic consultations in memory clinics. Further, we aimed to establish the optimal moment for each topic to be discussed during the diagnostic process. Methods We performed a three-round Delphi consensus study. Professionals (N = 80), patients (N = 66), and caregivers (N = 76) rated the importance of 44 informative topics through an online questionnaire. Consensus was defined as a topic rating of 6 or 7 on a 7-point Likert scale by ≥ 75% of each panel. In round 2 and 3, a survey was added to identify the optimal moment during the diagnostic process to discuss each topic. Results By round 3, consensus was achieved on 17 topics divided into four categories, information about (1) diagnostic testing, (2) test results, (3) diagnosis, and (4) practical implications. Eight additional topics showed significant differences between panels. Most notable panel differences regard the risk for developing dementia and the distinction between Alzheimer’s disease and dementia, which patients and caregivers evaluated as more important compared to professionals. The optimal moment to discuss topics during the diagnostic process was identified for the 17 core topics, and the eight topics with significant differences. Conclusions We present a core list of informative topics, which professionals, patients, and caregivers agree they should be discussed during the diagnostic process in a memory clinic. The topic list can support professionals and empower patients and caregivers during diagnostic physician-patient consultations. Electronic supplementary material The online version of this article (10.1186/s13195-019-0531-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Retinal thickness can be measured non-invasively with optical coherence tomography (OCT) and may offer compelling potential as a biomarker for Alzheimer's disease (AD). Retinal thinning is hypothesized to be a result of retrograde atrophy and/or parallel neurodegenerative processes. Changes in the visual pathway are of particular interest in posterior cortical atrophy (PCA), the most common atypical AD phenotype predominantly affecting the parietal-occipital cortices. We therefore evaluated retinal thickness as non-invasive biomarker of neurodegeneration in well-characterized participants with posterior cortical atrophy (PCA) and typical Alzheimer's disease (tAD).METHODS: Retinal thickness measures were acquired from 48 patient participants (N = 25 PCA; N = 23 tAD) fulfilling consensus diagnostic criteria and 70 age-matched controls. Participants were recruited between 2014 and 2016. All participants underwent optical coherence tomography (OCT) imaging, including measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular thickness (mRT). Participants did not show evidence of any significant ophthalmological conditions. Subgroup analyses were performed in participants with available MRI and CSF measures, providing evidence of neurodegeneration and underlying AD pathology respectively.RESULTS: There was no evidence of overall between-group differences in pRNFL thickness (mean PCA 98.7 ± 12.2; tAD 99.9 ± 8.7; controls 99.6 ± 10.0 μm, one-way analysis of variance (ANOVA) p = 0.92) or total mRT (mean PCA 266.9 ± 16.3; tAD 267.8 ± 13.6; controls 269.3 ± 13.6 μm, one-way ANOVA p = 0.75). Similarly, subgroup analysis with MRI biomarkers (PCA = 18, tAD = 17, controls = 31) showing neurodegeneration, and CSF biomarkers (PCA = 18, tAD = 14, controls = 13) supporting underlying AD pathology did not provide evidence of overall between-group differences in pRNFL or mRT measures (all p > 0.3).CONCLUSIONS: Retinal thickness did not discriminate tAD and PCA from controls or from one another despite unequivocal differences on standard clinical, neuro-imaging and CSF measures. Findings from this well-characterized sample, including cases with PCA, do not support the hypothesis that retinal neurodegeneration, measured using conventional OCT, is a useful biomarker for AD or PCA.

Background: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. Objective: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. Methods: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. Results: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. Conclusions: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

BackgroundAmyloid-β PET and CSF Aβ42yield discordant results in 10–20% of memory clinic patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic, and imaging features for amyloid positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-β status based on PET or CSF or whether this differs by disease stage.MethodsWe included 768 patients (subjective cognitive decline (SCD,n = 194), mild cognitive impairment (MCI,n = 127), dementia (AD and non-AD,n = 447) with amyloid-β PET and CSF Aβ42measurement within 1 year. Ninety-seven (13%) patients had discordant PET/CSF amyloid-β status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature and (ii) the patient feature adjusted for the status of the other amyloid modality.ResultsAPOE4, CSF tau, and p-tau had the highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR = 1.02 [1.01–1.04],pFDR = 0.03), MCI (OR = 1.05 [1.02–1.07],pFDR pFDR punc pFDR punc = 0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR = 1.17 [1.05–1.31],pFDR = 0.02) only predicted PET positivity in dementia.ConclusionAmyloid status based on either PET or CSF was predicted by different patient features, and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggest that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology.

Dementia is one of the main death leading causes worldwide and Alzheimer’s disease (AD) is its most common form. In postmortem examinations of AD brain tissue, extracellular deposits of proteins are observed, known as amyloid-beta (As) plaques. As plaques are characterized by their occurrence of beta-sheets and are, beside tau tangles, biological hallmarks in the postmortem diagnosis of AD. Little research on the detectability of As deposits in brain tissue using Raman spectroscopy has been published. Here, we examined formalin fixed, paraffin embedded tissue slices of AD and healthy control cases. The slices have been spectrally raster imaged with a step size smaller the size of a plaque using a commercial Raman spectroscope with a NIR laser source to obtain a hyperspectral map of the size of 0.5mm2. Specific band intensities including, among others, protein and lipid components were analyzed and afterward compared to the healthy control cases to study spectral differences. Further, As deposit locations could be precisely matched to the obtained spectral data by staining the same Raman imaged tissue slice with Thioflavin afterward. In addition, plaques can be co-localized by using histochemical stained adjacent tissue slices. In conclusion, we present new insights on spectral changes in the Raman fingerprint region of 950 to 1800cm-1 when analyzing the molecular composition of AD brain tissue.

BACKGROUND As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. OBJECTIVE The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. METHODS A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. RESULTS In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. CONCLUSIONS Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

Introduction Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer’s disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD). Methods We included three memory clinic SCD samples with available cerebrospinal fluid (CSF) biomaterial (IDIBAPS, Barcelona, Spain, n = 44; Amsterdam Dementia Cohort (ADC), The Netherlands, n = 50; DELCODE multicenter study, Germany, n = 42). CSF biomarkers (amyloid beta (Aβ)42, tau, and phosphorylated tau (ptau181)) were centrally analyzed in Amsterdam using prespecified cutoffs to define prevalence of pathological biomarker concentrations. We used logistic regression analysis in the combined sample across the three centers to investigate center effects with regard to likelihood of biomarker abnormality while taking potential common predictors (e.g., age, sex, apolipoprotein E (APOE) status, subtle cognitive deficits, depressive symptoms) into account. Results The prevalence of abnormal Aβ42, but not tau or ptau181, levels was different across centers (64% DELCODE, 57% IDIBAPS, 22% ADC; p

Introduction We aimed to describe clinician-patient communication in the diagnostic process of memory clinics, specifically clinician behavior known to facilitate knowledgeable participation of patients during consultations. Methods In this multicenter, observational study, we audio-recorded routine diagnostic consultations of 41 clinicians and 136 patients/caregivers at eight memory clinics. Patients/caregivers completed surveys after each audiotaped consultation. We used a study-specific coding scheme to categorize communication behavior. Results Clinicians often provided information on (results of) diagnostic testing. They infrequently invited questions and/or checked understanding. Clinician behavior to involve patients in decision-making about diagnostic testing was limited. Of note, patients/caregivers rarely expressed their information or involvement preferences. Yet, approximately, one quarter of them would have liked to receive more information. Discussion Involving patients more explicitly by means of shared decision-making could benefit the quality of care provided in memory clinics because it enables clinicians to attune the diagnostic workup to the individual patient's needs., Highlights • Considering patient preferences in the diagnostic process enables personalized care. • Knowledgeable participation in diagnostic consultations is therefore warranted. • Clinicians often provided information on diagnostic procedures and test results. • Yet, they showed limited behavior to promote patients' understanding. • And patients were seldom involved in decision-making about diagnostic testing.

Background Growing evidence suggests a role of occupation in the emergence and manifestation of dementia. Occupations are often defined by complexity level, although working environments and activities differ in several other important ways. We aimed to capture the multi-faceted nature of occupation through its measurement as a qualitative (instead of a quantitative) variable and explored its relationship with different types of dementia. Methods We collected occupational information of 2121 dementia patients with various suspected etiologies from the Amsterdam Dementia Cohort (age 67 ± 8, 57% male; MMSE 21 ± 5). Our final sample included individuals with Alzheimer’s disease (AD) dementia (n = 1467), frontotemporal dementia (n = 281), vascular dementia (n = 98), Lewy body disease (n = 174), and progressive supranuclear palsy/corticobasal degeneration (n = 101). Within the AD group, we used neuropsychological data to further characterize patients by clinical phenotypes. All participants were categorized into 1 of 11 occupational classes, across which we evaluated the distribution of dementia (sub)types with χ2 analyses. We gained further insight into occupation-dementia relationships through post hoc logistic regressions that included various demographic and health characteristics as explanatory variables. Results There were significant differences in the distribution of dementia types across occupation groups (χ2 = 85.87, p χ2 = 53.65, n.s.). Conclusions Relationships between occupation and dementia seem to exist beyond the complexity level, which offers new opportunities for disease prevention and improvement of occupational health policy.

Background Biomarkers such as cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have predictive value for progression to dementia in patients with mild cognitive impairment (MCI). The pre-dementia stage takes far longer, and the interpretation of biomarker findings is particular relevant for individuals who present at a memory clinic, but are deemed cognitively normal. The objective of the current study is to construct biomarker-based prognostic models for personalized risk of clinical progression in cognitively normal individuals presenting at a memory clinic. Methods We included 481 individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort. Prognostic models were developed by Cox regression with patient characteristics, MRI, and/or CSF biomarkers to predict clinical progression to MCI or dementia. We estimated 5- and 3-year individualized risks based on patient-specific values. External validation was performed on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an European dataset. Results Based on demographics only (Harrell’s C = 0.70), 5- and 3-year progression risks varied from 6% [3–11] and 4% [2–8] (age 55, MMSE 30) to 38% [29–49] and 28% [21–37] (age 70, MMSE 27). Normal CSF biomarkers strongly decreased progression probabilities (Harrell’s C = 0.82). By contrast, abnormal CSF markedly increased risk (5 years, 96% [56–100]; 3 years, 89% [44–99]). The CSF model could reclassify 58% of the individuals with an “intermediate” risk (35–65%) based on the demographic model. MRI measures were not retained in the models. Conclusion The current study takes the first steps in a personalized approach for cognitively normal individuals by providing biomarker-based prognostic models. Electronic supplementary material The online version of this article (10.1186/s13195-019-0487-y) contains supplementary material, which is available to authorized users.

Post-mortem in situ MRI has been used as an intermediate between brain histo(patho)logy and in vivo imaging. However, it is not known how comparable post-mortem in situ is to ante-mortem imaging. We report the unique situation of a patient with familial early-onset Alzheimer’s disease due to a PSEN1 mutation, who underwent ante-mortem brain MRI and post-mortem in situ imaging only 4 days apart. T1-weighted and diffusion MRI was performed at 3-Tesla at both time points. Visual atrophy rating scales, brain volume, cortical thickness and diffusion measures were derived from both scans and compared. Post-mortem visual atrophy scores decreased 0.5–1 point compared with ante-mortem, indicating an increase in brain volume. This was confirmed by quantitative analysis; showing a 27% decrease of ventricular and 7% increase of whole-brain volume. This increase was more pronounced in the cerebellum and supratentorial white matter than in grey matter. Furthermore, axial and radial diffusivity decreased up to 60% post-mortem whereas average fractional anisotropy of white matter increased approximately 10%. This unique case study shows that the process of dying affects several imaging markers. These changes need to be taken into account when interpreting post-mortem MRI to make inferences on the in vivo situation.

Objective To investigate whether subcortical grey matter atrophy predicts progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), and to compare subcortical volumes between AD, MCI and controls. To assess the correlation between subcortical grey matter volumes and severity of cognitive impairment. Methods We included 773 participants with three-dimensional T1-weighted MRI at 3 T, made up of 181 controls, who had subjective memory symptoms with normal cognition, 201 MCIs and 391 AD. During follow-up (2.0±0.9 years), 35 MCIs converted to AD (progressive MCI) and 160 MCIs remained stable (stable MCI). We segmented volumes of six subcortical structures of the amygdala, thalamus, caudate nucleus, putamen, globus pallidus and nucleus accumbens, and of the hippocampus, using FMRIBs integrated registration and segmentation tool. Results Analysis of variances, adjusted for sex and age, showed that all structures, except the globus pallidus, were smaller in AD than in controls. In addition, the amygdala, thalamus, putamen, nucleus accumbens and hippocampus were smaller in MCIs than in controls. Across groups, all subcortical greymatter volumes, except the globus pallidus, showed a positive correlation with cognitive function, as measured by Mini Mental State Examination (MMSE) (0.16

Objectives: To define CSF β-amyloid 1–42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice.Methods: We included 433 participants (57 controls, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C]PiB-PET images.Results: Amyloid-PET–based calculated CSF Aβ42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had negative amyloid-PET and abnormal CSF Aβ42 levels.Conclusions: Amyloid-PET–based CSF Aβ42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ42 and a negative amyloid-PET.Classification of evidence: This study provides Class II evidence that an amyloid-PET–based CSF Aβ42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%.

Background: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. Objective: This study aims to investigate the added prognostic value of AD CSF biomarkers. Methods: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information. Results: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. Conclusion: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

Background Amyloid pathology is the pathological hallmark in Alzheimer’s disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. Methods From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. Results We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. Conclusions A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline. Electronic supplementary material The online version of this article (10.1186/s13195-018-0406-7) contains supplementary material, which is available to authorized users.

INTRODUCTION: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. METHODS: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post-positron emission tomography diagnosis and management change between "AUC-consistent" and "AUC-inconsistent" patients. RESULTS: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post-positron emission tomography diagnosis (28%-21%) and management (32%-17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). DISCUSSION: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.

Background Disclosure of amyloid positron emission tomography (PET) results to individuals without dementia has become standard practice in secondary prevention trials and also increasingly occurs in clinical practice. However, this is controversial given the current lack of understanding of the predictive value of a PET result at the individual level and absence of disease-modifying treatments. In this study, we systematically reviewed the literature on the disclosure of amyloid PET in cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) in both research and clinical settings. Methods We performed a systematic literature search of four scientific databases. Two independent reviewers screened the identified records and selected relevant articles. Included articles presented either empirical data or theoretical data (i.e. arguments in favor or against amyloid status disclosure). Results from the theoretical data were aggregated and presented per theme. Results Of the seventeen included studies, eleven reported empirical data and six provided theoretical arguments. There was a large variation in the design of the empirical studies, which were almost exclusively in the context of cognitively normal trial participants, comprising only two prospective cohort studies quantitatively assessing the psychological impact of PET result disclosure which showed a low risk of psychological harm after disclosure. Four studies showed that both professionals and cognitively normal individuals support amyloid PET result disclosure and underlined the need for clear disclosure protocols. From the articles presenting theoretical data, we identified 51 ‘pro’ and ‘contra’ arguments. Theoretical arguments in favor or against disclosure were quite consistent across population groups and settings. Arguments against disclosure focused on the principle of non-maleficence, whereas its psychological impact and predictive value is unknown. Important arguments in favor of amyloid disclosure are the patients right to know (patient autonomy) and that it enables early future decision making. Discussion Before amyloid PET result disclosure in individuals without dementia in a research or clinical setting is ready for widespread application, more research is needed about its psychological impact, and its predictive value at an individual level. Finally, communication materials and strategies to support disclosure of amyloid PET results should be further developed and prospectively evaluated. Electronic supplementary material The online version of this article (10.1186/s13195-018-0398-3) contains supplementary material, which is available to authorized users.

Introduction Individuals with subjective cognitive decline (SCD) are at increased risk of Alzheimer's disease and could benefit from a prevention strategy targeting lifestyle factors. Making a program available through the Internet gives a widespread reach at low cost, but suboptimal adherence is a major threat to effectiveness. As a first step in developing an online lifestyle program (OLP), we aimed to identify factors that are barriers and/or facilitators for the use of an OLP in individuals with SCD in three European countries. Methods As part of the Euro-SCD project, SCD subjects were recruited at memory clinics in the Netherlands, Germany, and Spain. We combined quantitative and qualitative methods, using a mixed methods approach. We conducted an online 18-item survey on the preferences of SCD patients for an OLP (N = 238). In addition, we held semi-structured interviews (N = 22) to gain in-depth understanding of factors acting as a facilitator and/or barrier for intended use of an OLP. Audio recordings were transcribed verbatim. Content analysis was performed. Results One hundred seventy-six individuals completed the survey (response rate 74%). Almost all participants regularly use the Internet (97%). Participants reported trustworthiness (93%), user-friendliness (91%), and up-to-date information (88%) as main facilitators, whereas having contact with other users (26%), needing an account (21%), and assignments (16%) were reported as barriers. Barriers differed slightly between countries, but facilitators were largely similar. In-depth interviews revealed that both program characteristics (e.g., trustworthiness, user-friendliness, and personalization) and personal factors (e.g., expectancy to receive negative feedback) are likely to influence the intended use of an OLP. Discussion Involving users provided in-depth understanding of factors associated with the intended use of an OLP for brain health. Both program characteristics and personal factors are likely to influence the use of an OLP. Based on this input from the end-users, we will develop an OLP for individuals with SCD., Highlights • Almost all participants believe that healthy lifestyle contributes to brain health. • Almost all participants use the Internet daily, on all types of devices. • Barriers or facilitators can be program characteristics as well as personal factors. • Trustworthiness, user-friendliness, and personalization are important facilitators. • One online lifestyle program for different European countries seems feasible.

Aim: To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington’s disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. Methods: Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. Results: The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. Conclusion: Relative to other neurodegenerative diseases, the clinical use of FDG-PET in ALS and HD is still in its infancy. Once validated by disease-control studies, FDG-PET might represent a potentially useful biomarker for ALS diagnosis. FDG-PET is presently not justified as a routine investigation to predict conversion to HD, nor to detect evidence of brain dysfunction justifying cognitive decline in ALS and HD.

BACKGROUND: While most patients with Alzheimer's disease (AD) present with memory complaints, 30% of patients with early disease onset present with non-amnestic symptoms. This atypical presentation is thought to be caused by a different spreading of neurofibrillary tangles (NFT) than originally proposed by Braak and Braak. Recent studies suggest a prominent role for neuroinflammation in the spreading of tau pathology.METHODS: We aimed to explore whether an atypical spreading of pathology in AD is associated with an atypical distribution of neuroinflammation. Typical and atypical AD cases were selected based on both NFT distribution and amnestic or non-amnestic clinical presentation. Immunohistochemistry was performed on the temporal pole and superior parietal lobe of 10 typical and 9 atypical AD cases. The presence of amyloid-beta (N-terminal; IC16), pTau (AT8), reactive astrocytes (GFAP), microglia (Iba1, CD68, and HLA-DP/DQ/DR), and complement factors (C1q, C3d, C4b, and C5b-9) was quantified by image analysis. Differences in lobar distribution patterns of immunoreactivity were statistically assessed using a linear mixed model.RESULTS: We found a temporal dominant distribution for amyloid-beta, GFAP, and Iba1 in both typical and atypical AD. Distribution of pTau, CD68, HLA-DP/DQ/DR, C3d, and C4b differed between AD variants. Typical AD cases showed a temporal dominant distribution of these markers, whereas atypical AD cases showed a parietal dominant distribution. Interestingly, when quantifying for the number of amyloid-beta plaques instead of stained surface area, atypical AD cases differed in distribution pattern from typical AD cases. Remarkably, plaque morphology and localization of neuroinflammation within the plaques was different between the two phenotypes.CONCLUSIONS: Our data show a different localization of neuroinflammatory markers and amyloid-beta plaques between AD phenotypes. In addition, these markers reflect the atypical distribution of tau pathology in atypical AD, suggesting that neuroinflammation might be a crucial link between amyloid-beta deposits, tau pathology, and clinical symptoms.

In-vivo labeling of retinal amyloid-beta(Aβ) and tau has potential as non-invasive biomarker for Alzheimer’s disease (AD). However, literature on the presence of Aβ and phosphorylated tau (pTau) in AD retinas is inconclusive. We therefore assessed the presence of Aβ and pTau in post-mortem retinas in 6 AD and 6 control cases who donated brains and eyes to the Netherlands Brain Bank. Neuropathological diagnosis of AD was made according to NIA-AA criteria. Formalin fixed retinas were dissected in quadrants and cross-sections of medial and superior retinas were made. Immuno-histochemical stainings were performed for Aβ, amyloid precursor protein (APP) and pTau. To assess translation to an in-vivo set up using curcumin as labelling fluorophore, co-stainings with curcumin were performed. No typical Aβ-plaques and neurofibrillary tangles, like in the cerebral cortex, were observed in AD retinas. A diffuse immunoreactive signal for pTau was increased in the inner and outer plexiform layers of the retina in AD cases compared to control cases with absence of cerebral amyloid pathology. Immunostaining with anti-Aβ and anti-APP antibodies yielded signal in ganglion cells, amacrine cells, horizontal cells and Müller cells in both control and AD cases. We observed small extracellular deposits positive for anti-Aβ antibodies 12F4 and 6E10 and negative for 4G8 and curcumin. A subset of these deposits could be characterized as corpora amylacea. In conclusion we found that retinal manifestations of AD pathology appear to be different compared to cerebral AD pathology. Using a qualitative cross-sectional approach, we did not find Aβ/APP related differences in the retina between AD and control subjects. In contrast, tau related changes were found to be present in cases with cerebral AD pathology, suggesting retinal tau as a potential biomarker for AD.

PURPOSE: To review literature until November 2015 and reach a consensus on whether automatic semi-quantification of brain FDG-PET is useful in the clinical setting for neurodegenerative disorders. METHODS: A literature search was conducted in Medline, Embase, and Google Scholar. Papers were selected with a lower limit of 30 patients (no limits with autopsy confirmation). Consensus recommendations were developed through a Delphi procedure, based on the expertise of panelists, who were also informed about the availability and quality of evidence, assessed by an independent methodology team. RESULTS: Critical outcomes were available in nine among the 17 papers initially selected. Only three papers performed a direct comparison between visual and automated assessment and quantified the incremental value provided by the latter. Sensitivity between visual and automatic analysis is similar but automatic assessment generally improves specificity and marginally accuracy. Also, automated assessment increases diagnostic confidence. As expected, performance of visual analysis is reported to depend on the expertise of readers. CONCLUSIONS: Tools for semi-quantitative evaluation are recommended to assist the nuclear medicine physician in reporting brain FDG-PET pattern in neurodegenerative conditions. However, heterogeneity, complexity, and drawbacks of these tools should be known by users to avoid misinterpretation. Head-to-head comparisons and an effort to harmonize procedures are encouraged. ispartof: European Journal Of Nuclear Medicine And Molecular Imaging vol:45 issue:9 pages:1557-1566 ispartof: location:Germany status: published

Introduction We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. Methods We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1–42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. Results Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau. Discussion The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods., Highlights • Method comparison of 137 CSF samples collected in eight nonacademic memory clinics. • Innotest and Elecsys strongly correlated: ρ = 0.94 Aβ42; 0.98 t-tau; 0.98 p-tau. • Concordances of biomarker abnormalities: 97% Aβ42; 96% t-tau and p-tau. • Concordance of NIA-AA–based Alzheimer's disease profile (Aβ42 decreased and p-tau increased): 89%. • Preanalytical protocol deviations did not show effects on biomarker correlations.