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Background and ObjectivesWe assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy.MethodsWe studied 499 participants aged 60–88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education.ResultsIn the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers.DiscussionNovelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity.

BACKGROUND: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention.OBJECTIVE: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment.METHODS: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed.RESULTS: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P CONCLUSION: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Purpose Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. Method A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer’s disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. Conclusion This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

BACKGROUND: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.METHODS: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups.RESULTS: The ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.CONCLUSION: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy.TRIAL REGISTRATION: DRKS00007966, 04/05/2015, retrospectively registered.

Background In preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. Methods We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. Results In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs. Conclusions These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

The cerebral waste clearance system (i.e, glymphatic or intramural periarterial drainage) works through a network of perivascular spaces (PVS). Dysfunction of this system likely contributes to aggregation of Amyloid-β and subsequent toxic plaques in Alzheimer's disease (AD). A promising, non-invasive technique to study this system is MRI, though applications in dementia are still scarce. This review focusses on recent non-contrast enhanced (non-CE) MRI techniques which determine and visualise physiological aspects of the clearance system at multiple levels, i.e., cerebrospinal fluid flow, PVS-flow and interstitial fluid movement. Furthermore, various MRI studies focussing on aspects of the clearance system which are relevant to AD are discussed, such as studies on ageing, sleep alterations, and cognitive decline. Additionally, the complementary function of non-CE to CE methods is elaborated upon. We conclude that non-CE studies have great potential to determine which parts of the waste clearance system are affected by AD and in which stages of cognitive impairment dysfunction of this system occurs, which could allow future clinical trials to target these specific mechanisms.

The cerebral waste clearance system (i.e, glymphatic or intramural periarterial drainage) works through a network of perivascular spaces (PVS). Dysfunction of this system likely contributes to aggregation of Amyloid-β and subsequent toxic plaques in Alzheimer's disease (AD). A promising, non-invasive technique to study this system is MRI, though applications in dementia are still scarce. This review focusses on recent non-contrast enhanced (non-CE) MRI techniques which determine and visualise physiological aspects of the clearance system at multiple levels, i.e., cerebrospinal fluid flow, PVS-flow and interstitial fluid movement. Furthermore, various MRI studies focussing on aspects of the clearance system which are relevant to AD are discussed, such as studies on ageing, sleep alterations, and cognitive decline. Additionally, the complementary function of non-CE to CE methods is elaborated upon. We conclude that non-CE studies have great potential to determine which parts of the waste clearance system are affected by AD and in which stages of cognitive impairment dysfunction of this system occurs, which could allow future clinical trials to target these specific mechanisms.

PURPOSE: Retinal microvascular abnormalities measured on retinal images are a potential source of prognostic biomarkers of vascular changes in the neurodegenerating brain. We assessed the presence of these abnormalities in Alzheimer's dementia and mild cognitive impairment (MCI) using ultra-widefield (UWF) retinal imaging.METHODS: UWF images from 103 participants (28 with Alzheimer's dementia, 30 with MCI, and 45 with normal cognition) underwent analysis to quantify measures of retinal vascular branching complexity, width, and tortuosity.RESULTS: Participants with Alzheimer's dementia displayed increased vessel branching in the midperipheral retina and increased arteriolar thinning. Participants with MCI displayed increased rates of arteriolar and venular thinning and a trend for decreased vessel branching.CONCLUSIONS: Statistically significant differences in the retinal vasculature in peripheral regions of the retina were observed among the distinct cognitive stages. However, larger studies are required to establish the clinical importance of our findings. UWF imaging may be a promising modality to assess a larger view of the retinal vasculature to uncover retinal changes in Alzheimer's disease.TRANSLATIONAL RELEVANCE: This pilot work reports an investigation into which retinal vasculature measurements may be useful surrogate measures of cognitive decline, as well as technical developments (e.g., measurement standardization), that are first required to establish their recommended use and translational potential.

Background With the shift of research focus towards the pre-dementia stage of Alzheimer’s disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. Conclusions Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status.

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.

Surgical patients are at high risk of developing postoperative cognitive dysfunction (POCD) and postoperative delirium (POD). POCD and POD are associated with increased morbidity and mortality and worsening functional outcomes leading to severe socioeconomic consequences for the patient and the society in general. Magnetic resonance imaging (MRI) offers a unique opportunity to study the anatomy and function of the brain. MRI thus plays an important role in elucidating the neuronal component of POCD and POD. Our aim has been to systematically gather MRI findings that are related to POCD and POD. Systematic searches were conducted in PubMed, EMBASE, and PsycINFO: MRI studies investigating patients with POCD as identified by perioperative cognitive testing or patients with delirium identified postoperatively by the Confusion Assessment Method. A total of ten eligible papers were included with a total of 269 surgical patients, 36 patient controls, and 55 healthy controls who all underwent MRI examination. These studies suggested that reduction of thalamic and hippocampal volumes and reduction of cerebral blood flow may be associated with POCD, while presurgery/preexisting and postoperative white matter pathology may be associated with POD. However, the evidence from these studies is rather weak. Future MRI studies are warranted to verify the current findings.

There is growing support that cerebrovascular reactivity (CVR) in response to a vasodilatory challenge, also defined as the cerebrovascular reserve, is reduced in Alzheimer's disease dementia. However, this is less clear in patients with mild cognitive impairment (MCI). The current standard analysis may not reflect subtle abnormalities in CVR. In this study, we aimed to investigate vasodilatory-induced changes in the topology of the cerebral blood flow correlation (CBFcorr) network to study possible network-related CVR abnormalities in MCI. For this purpose, four CBFcorr networks were constructed: two using CBF SPECT data at baseline and under the vasodilatory challenge of acetazolamide (ACZ), obtained from a group of 26 MCI patients; and two equivalent networks from a group of 26 matched cognitively normal controls. The mean strength of association (SA) and clustering coefficient (C) were used to evaluate ACZ-induced changes on the topology of CBFcorr networks. We found that cognitively normal adults and MCI patients show different patterns of C and SA changes. The observed differences included the medial prefrontal cortices and inferior parietal lobe, which represent areas involved in MCI's cognitive dysfunction. In contrast, no substantial differences were detected by standard CVR analysis. These results suggest that graph theoretical analysis of ACZ-induced changes in the topology of the CBFcorr networks allows the identification of subtle network-related CVR alterations in MCI, which couldn't be detected by the standard approach., Highlights • Subtle alterations in cerebrovascular reactivity in MCI by graph theoretical analysis. • Graph theoretical analysis seems to be sensitive to subtle abnormalities. • The standard approach could be insufficient for capturing subtle abnormal changes.

Supplemental Digital Content is available in the text., Background and Purpose— Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease–related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods— Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network–based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results— The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

INTRODUCTION: Magnetic resonance imaging (MRI) and electroencephalography (EEG) are a promising means to an objectified assessment of cognitive impairment in Alzheimer's disease (AD). Individually, however, these modalities tend to lack precision in both AD diagnosis and AD staging. A joint MRI-EEG approach that combines structural with functional information has the potential to overcome these limitations.MATERIALS AND METHODS: This cross-sectional study systematically investigated the link between MRI and EEG markers and the global cognitive status in early AD. We hypothesized that the joint modalities would identify cognitive deficits with higher accuracy than the individual modalities. In a cohort of 111 AD patients, we combined MRI measures of cortical thickness and regional brain volume with EEG measures of rhythmic activity, information processing and functional coupling in a generalized multiple regression model. Machine learning classification was used to evaluate the markers' utility in accurately separating the subjects according to their cognitive score.RESULTS: We found that joint measures of temporal volume, cortical thickness, and EEG slowing were well associated with the cognitive status and explained 38.2% of ifs variation. The inclusion of the covariates age, sex, and education considerably improved the model. The joint markers separated the subjects with an accuracy of 84.7%, which was considerably higher than by using individual modalities.CONCLUSIONS: These results suggest that including joint MRI-EEG markers may be beneficial in the diagnostic workup, thus allowing for adequate treatment. Further studies in larger populations, with a longitudinal design and validated against functional-metabolic imaging are warranted to confirm the results.

Postoperative delirium (POD) and postoperative cognitive decline (POCD) are common in elderly patients. The aim of the present review was to explore the association of neurodegenerative and neurovascular changes with the occurrence of POD and POCD. Fifteen MRI studies were identified by combining multiple search terms for POD, POCD, and brain imaging. These studies described a total of 1,422 patients and were all observational in design. Neurodegenerative changes (global and regional brain volumes) did not show a consistent association with the occurrence of POD (four studies) or POCD (two studies). In contrast, neurovascular changes (white matter hyperintensities and cerebral infarcts) were more consistently associated with the occurrence of POD (seven studies) and POCD (five studies). In conclusion, neurovascular changes appear to be consistently associated with the occurrence of POD and POCD, and may identify patients at increased risk of these conditions. Larger prospective studies are needed to study the consistency of these findings and to unravel the underlying pathophysiological mechanisms.

BACKGROUND: Several studies found that patients with atrial fibrillation (AF) have an increased risk of cognitive decline and dementia over time. However, the magnitude of the problem, associated risk factors and underlying mechanisms remain unclear. METHODS: This article describes the design and methodology of the Swiss Atrial Fibrillation (Swiss-AF) Cohort Study, a prospective multicentre national cohort study of 2400 patients across 13 sites in Switzerland. Eligible patients must have documented AF. Main exclusion criteria are the inability to provide informed consent and the presence of exclusively short episodes of reversible forms of AF. All patients undergo extensive phenotyping and genotyping, including repeated assessment of cognitive functions, quality of life, disability, electrocardiography and cerebral magnetic resonance imaging. We also collect information on health related costs, and we assemble a large biobank. Key clinical outcomes in Swiss-AF are death, stroke, systemic embolism, bleeding, hospitalisation for heart failure and myocardial infarction. Information on outcomes and updates on other characteristics are being collected during yearly follow-up visits. RESULTS: Up to 7 April 2017, we have enrolled 2133 patients into Swiss-AF. With the current recruitment rate of 15 to 20 patients per week, we expect that the target sample size of 2400 patients will be reached by summer 2017. CONCLUSION: Swiss-AF is a large national prospective cohort of patients with AF in Switzerland. This study will provide important new information on structural and functional brain damage in patients with AF and on other AF related complications, using a large variety of genetic, phenotypic and health economic parameters.

BACKGROUND: The vascular contributions to neurodegeneration and neuroinflammation may be assessed by magnetic resonance imaging (MRI) and ultrasonography (US). This review summarises the methodology for these widely available, safe and relatively low cost tools and analyses recent work highlighting their potential utility as biomarkers for differentiating subtypes of cognitive impairment and dementia, tracking disease progression and evaluating response to treatment in various neurocognitive disorders. ----- METHODS: At the 9th International Congress on Vascular Dementia (Ljubljana, Slovenia, October 2015) a writing group of experts was formed to review the evidence on the utility of US and arterial spin labelling (ASL) as neurophysiological markers of normal ageing, vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Original articles, systematic literature reviews, guidelines and expert opinions published until September 2016 were critically analysed to summarise existing evidence, indicate gaps in current knowledge and, when appropriate, suggest standards of use for the most widely used US and ASL applications. ----- RESULTS: Cerebral hypoperfusion has been linked to cognitive decline either as a risk or an aggravating factor. Hypoperfusion as a consequence of microangiopathy, macroangiopathy or cardiac dysfunction can promote or accelerate neurodegeneration, blood-brain barrier disruption and neuroinflammation. US can evaluate the cerebrovascular tree for pathological structure and functional changes contributing to cerebral hypoperfusion. Microvascular pathology and hypoperfusion at the level of capillaries and small arterioles can also be assessed by ASL, an MRI signal. Despite increasing evidence supporting the utility of these methods in detection of microvascular pathology, cerebral hypoperfusion, neurovascular unit dysfunction and, most importantly, disease progression, incomplete standardisation and missing validated cut-off values limit their use in daily routine. ----- CONCLUSIONS: US and ASL are promising tools with excellent temporal resolution, which will have a significant impact on our understanding of the vascular contributions to VCI and AD and may also be relevant for assessing future prevention and therapeutic strategies for these conditions. Our work provides recommendations regarding the use of non-invasive imaging techniques to investigate the functional consequences of vascular burden in dementia.

The use of biomarkers (BMs) for accurate diagnosis of Alzheimer's disease (AD) has been proposed by recent diagnostic criteria; however, their maturity is not sufficient to grant implementation in the clinical routine. A proper diagnostic process requires not only confirmation of the disease but also the exclusion of similar disorders entering differential diagnosis, like dementia with Lewy bodies (DLB). This review is aimed at evaluating the clinical validity of 123I-ioflupane brain single photon emission tomography and 123I-MIBG cardiac scintigraphy as imaging BMs for DLB. For this purpose, we used an adapted version of the 5-phase oncology framework for BMs development. A review of the literature was conducted using homogenous search criteria with other BMs addressed in parallel reviews. Results of our literature search showed that the rationale for the use of both BMs in the differential diagnosis of DLB and AD is strong (phase 1) and that they allow a good discrimination ability (phase 2), but studies investigating BMs distribution antemortem and postmortem on pathology are lacking. Moreover, thresholds for test positivity have not been defined for 123I-MIBG. The 2 BMs have not been yet assessed in early phases of DLB and AD (phase 3). No phase 4 and phase 5 studies have so far been carried out. This review highlights the priorities to address in future investigations to enable the proper use of 123I-ioflupane and 123I-MIBG for the differential diagnosis of dementia.

The European DTI Study on Dementia (EDSD) is a multicenter framework created to study the diagnostic accuracy and inter-site variability of DTI-derived markers in patients with manifest and prodromal Alzheimer's disease (AD). The dynamically growing database presently includes 493 DTI, 512 T1-weighted MRI, and 300 FLAIR scans from patients with AD dementia, patients with Mild Cognitive Impairment (MCI) and matched Healthy Controls, acquired on 13 different scanner platforms. The imaging data is publicly available, along with the subjects' demographic and clinical characterization. Detailed neuropsychological information, cerebrospinal fluid information on biomarkers and clinical follow-up diagnoses are included for a subset of subjects. This paper describes the rationale and structure of the EDSD, summarizes the available data, and explains how to gain access to the database. The EDSD is a useful database for researchers seeking to investigate the contribution of DTI to dementia diagnostics.

BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.