Showing papers by "Giovanni B. Frisoni published in 2014"

Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria

Abstract: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

Brain connectivity in neurodegenerative diseases—from phenotype to proteinopathy

Abstract: Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.

A Standardized [18F]-FDG-PET Template for Spatial Normalization in Statistical Parametric Mapping of Dementia

Abstract: [18F]-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) is a widely used diagnostic tool that can detect and quantify pathophysiology, as assessed through changes in cerebral glucose metabolism. [18F]-FDG PET scans can be analyzed using voxel-based statistical methods such as Statistical Parametric Mapping (SPM) that provide statistical maps of brain abnormalities in single patients. In order to perform SPM, a "spatial normalization" of an individual's PET scan is required to match a reference PET template. The PET template currently used for SPM normalization is based on [15O]-H2O images and does not resemble either the specific metabolic features of [18F]-FDG brain scans or the specific morphological characteristics of individual brains affected by neurodegeneration. Thus, our aim was to create a new [18F]-FDG PET aging and dementia-specific template for spatial normalization, based on images derived from both age-matched controls and patients. We hypothesized that this template would increase spatial normalization accuracy and thereby preserve crucial information for research and diagnostic purposes. We investigated the statistical sensitivity and registration accuracy of normalization procedures based on the standard and new template-at the single-subject and group level-independently for subjects with Mild Cognitive Impairment (MCI), probable Alzheimer's Disease (AD), Frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB). We found a significant statistical effect of the population-specific FDG template-based normalisation in key anatomical regions for each dementia subtype, suggesting that spatial normalization with the new template provides more accurate estimates of metabolic abnormalities for single-subject and group analysis, and therefore, a more effective diagnostic measure.

Subregional basal forebrain atrophy in Alzheimer's disease: a multicenter study.

Abstract: Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Abstract: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Determinants of Health and Disability in Ageing Population: The COURAGE in Europe Project (Collaborative Research on Ageing in Europe)

Abstract: COURAGE in Europe was a 3-year project involving 12 partners from four European countries and the World Health Organization. It was inspired by the pressing need to integrate international studies on disability and ageing in light of an innovative perspective based on a validated data-collection protocol. COURAGE in Europe Project collected data on the determinants of health and disability in an ageing population, with specific tools for the evaluation of the role of the built environment and social networks on health, disability, quality of life and well-being. The main survey was conducted by partners in Finland, Poland and Spain where the survey has been administered to a sample of 10 800 persons, which was completed in March 2012. The newly developed and validated COURAGE Protocol for Ageing Studies has proven to be a valid tool for collecting comparable data in ageing population, and the COURAGE in Europe Project has created valid and reliable scientific evidence, demonstrating cross-country comparability, for disability and ageing research and policy development. It is therefore recommended that future studies exploring determinants of health and disability in ageing use the COURAGE-derived methodology. Copyright © 2013 John Wiley & Sons, Ltd. Key Practitioner Message COURAGE in Europe Project collected data on the determinants of health and disability in an ageing population, with specific tools for the evaluation of the role of built environment and social networks on health, disability quality of life and well-being. The COURAGE Protocol for Ageing Studies has proven to be a valid tool for collecting comparable data in the ageing population. The COURAGE in Europe Consortium recommends that future studies exploring determinants of health and disability in ageing use COURAGE-derived methodology.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease

Abstract: Background: Regulatory qualification of a biomarker for a defined context of use provides scientifically robustassurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. Methods: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampalvolumeasabiomarkerforenrichingclinicaltrialsinsubjectswithmildcognitiveimpairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer’s Disease Neuroimaging Initiative data.

The road ahead to cure Alzheimer’s disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations

Abstract: Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for "prodromal AD" and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

Fractional Anisotropy Changes in Alzheimer's Disease Depend on the Underlying Fiber Tract Architecture: A Multiparametric DTI Study using Joint Independent Component Analysis

Abstract: Diffusion tensor imaging (DTI) allows the simultaneous measurement of several diffusion indices that provide complementary information on the substrate of white matter alterations in neurodegenerative diseases. These indices include fractional anisotropy (FA) as measure of fiber tract integrity, and the mode of anisotropy (Mode) reflecting differences in the shape of the diffusion tensor. We used a multivariate approach based on joint independent component analysis of FA and Mode in a large sample of 138 subjects with Alzheimer's disease (AD) dementia, 37 subjects with cerebrospinal fluid biomarker positive mild cognitive impairment (MCI-AD), and 153 healthy elderly controls from the European DTI Study on Dementia to comprehensively study alterations of microstructural white matter integrity in AD dementia and predementia AD. We found a parallel decrease of FA and Mode in intracortically projecting fiber tracts, and a parallel increase of FA and Mode in the corticospinal tract in AD patients compared to controls. Subjects with MCI-AD showed a similar, but spatially more restricted pattern of diffusion changes. Our findings suggest an early axonal degeneration in intracortical projecting fiber tracts in dementia and predementia stages of AD. An increase of Mode, parallel to an increase of FA, in the corticospinal tract suggests a more linear shape of diffusion due to loss of crossing fibers along relatively preserved cortico-petal and cortico-fugal fiber tracts in AD. Supporting this interpretation, we found three populations of fiber tracts, namely cortico-petal and cortico-fugal, commissural, and intrahemispherically projecting fiber tracts, in the peak area of parallel FA and Mode increase.

Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers

Abstract: Background To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin ( GRN ) mutation carriers. Methods Ten cognitively normal subjects (five mutation carriers, GRN +; years to estimated disease onset: 12 ± 7; five mutation noncarriers, GRN −) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. Results GRN + showed smaller cortical thickness than GRN − in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. Conclusion Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.

Erratum to “A Survey of FDG- and Amyloid-PET Imaging in Dementia and GRADE Analysis”

Abstract: The authors' names were incorrectly listed as Perani Daniela, Schillaci Orazio, Padovani Alessandro, Nobili Flavio Mariano, Iaccarino Leonardo, Della Rosa Pasquale Anthony, Frisoni Giovanni, and Caltagirone Carlo; this error is corrected here. The addresses have been corrected.

Establishing Magnetic Resonance Images Orientation for the EADC‐ADNI Manual Hippocampal Segmentation Protocol

Abstract: BACKGROUND AND PURPOSE An effort to define and validate a Harmonized Protocol for standard hippocampal segmentation is being carried out. We wished to estimate the effect of magnetic resonance image (MRI) spatial orientation on manual hippocampal segmentations to define optimal standard orientation of MRIs for hippocampal volumetry. METHODS Three expert tracers segmented twice the hippocampi of 10 ADNI subjects on MRI slices oriented perpendicular to the anterior-posterior commissure (AC-PC) line and the long hippocampal axes plane, following internationally harmonized landmarks. We computed intra and interrater reliability figures for total volumes and similarity coefficients. RESULTS Total volume reliability was similar for both orientations. Similarity coefficients were significantly higher for the AC-PC orientation (exact P = 0.002). DISCUSSION These data show that AC-PC orientation is slightly more reliable for manual segmentations, possibly due to better visualization of the cerebrospinal fluid spaces separating hippocampal head and amygdala. A Delphi panel of experts has used these data to decide on the optimal orientation for a Harmonized Protocol for hippocampal segmentation.

HarP: The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation. A standard of reference from a global working group

Abstract: This special issue of Alzheimer’s & Dementia marks the completion of an initiative kick-started as long as 6 years ago. At the time, hippocampal atrophy was regarded by International Working Group criteria as one of the biomarkers for the early diagnosis of Alzheimer’s disease (AD) [1], academic memory clinics were pioneering its use in real life diagnostic studies [2–4], and clinical trials of disease modifiers were starting to use hippocampal atrophy rates as a secondary outcome measure [5]. Widely different measurement protocols prevented the comparison of diagnostic accuracy and biologic drug efficacy. Standard operating procedures were clearly needed—an effort greatly facilitated by the availability of ADNI (Alzheimer’s Disease Neuroimaging Initiative) harmonized image acquisition parameters and procedures [6]. The initiative was kicked off at a feasibility workshop organized by the Alzheimer’s Association in Chicago in 2008 where ADNI and European Alzheimer’s Disease Consortium key members took part, and experts in imaging biomarkers. A survey was set out to identify the 12 most frequently used protocols for hippocampal segmentation in the Alzheimer’s literature and differences in image treatment procedures and anatomical landmarks (Fig. 1), a mandatory step to develop a harmonized protocol [7]. In an exercise reminiscent of a LEGO block game, the preliminary phase did a virtual break down of the hippocampi resulting from the aforementioned protocols in a finite number of three-dimensional (3D)-units summarizing their entire anatomical variability. Biometric features of the 3D-units were then empirically quantitated (e.g. measurement stability, contribution to Alzheimer’s-associated atrophy) and fed to a panel of world experts, including the developers of the 12 originally selected protocols, whowere charged of coming out with a unique and harmonized segmentation protocol. Thanks to a Delphi procedure adapted to accommodate quantitative information, it took experts five rounds to converge onto a definitive version (the harmonized protocol—HarP). Five expert researchers on hippocampal segmentation (“master tracers”) were then asked to segment 40 representative hippocampi taken from the ADNI database following the HarP, thatwould beused as the standard of truth of any ensuing procedure (so-called “benchmark labels”). Fourteen tracers coming from 12 imaging laboratories from eight countries in three continents which had not been exposed to the development of the HarP were asked to segment another set of 40 hippocampi representative of the ADNI dataset, trained and qualified to segment following the HarP on an ad hoc webbased environment, and asked to re-trace the same ADNI hippocampi following the HarP. An appropriately balanced design allowed to test the concurrent validity of the HarP versus local protocols, and compare the error variance of hippocampal volume estimates due to theHarPwith other sources of error. Finally, HarP hippocampal volumes were validated versus pathological findings in a sample of brains where both high-resolution structural magnetic resonance imaging and a post-mortem examination were available, and publicly available HarP labels were expanded to a large set of 270 ADNI hippocampi to allow the training of automated segmentation algorithms based on machine learning technology. Clearly, participation to the project was effortful and time consuming at all levels. Protocol developers were engaged in multiple hour-long teleconferences to tease out the finest details of their protocols, master tracers were pressed to carry out the assigned segmentations in due time, Delphi panelists were forced to go through similar sets of questions and issues over and over again until the convergence of most panelists, and naive tracers had to segment dozens (some of them hundreds) of hippocampi in a restricted time frame. Everyone’s engagement was astoundingly intense. Importantly, the HarP is the result of the concerted effort of many minds (Fig. 2). The working group met twice a year for the past 5 years and at each meeting the project was finetuned and its experimental design continuously improved thanks to input from participants. An off-workplan expansion of the number of segmented hippocampi was required by automated segmentation algorithm developers, and duly carried out. A large and representative set of certified hippocampal labels obtained with the HarP is now publicly available in the web that can be used to train and qualify human tracers and automated algorithms. Thanks to the HarP, it is now possible to directly compare the segmentation accuracy of the many automated

Imaging as a biomarker in drug discovery for Alzheimer’s disease: is MRI a suitable technology?

Abstract: This review provides perspectives on the utility of magnetic resonance imaging (MRI) as a neuroimaging approach in the development of novel treatments for Alzheimer’s disease These considerations were generated in a roundtable at a recent Wellcome Trust meeting that included experts from academia and industry It was agreed that MRI, either structural or functional, could be used as a diagnostic, for assessing worsening of disease status, for monitoring vascular pathology, and for stratifying clinical trial populations It was agreed also that MRI implementation is in its infancy, requiring more evidence of association with the disease states, test-retest data, better standardization across multiple clinical sites, and application in multimodal approaches which include other imaging technologies, such as positron emission tomography, electroencephalography, and magnetoencephalography

Hippocampal atrophy in people with memory deficits: results from the population-based IPREA study.

Abstract: Background: Clinical studies have shown that hippocampal atrophy is present before dementia in people with memory deficits and can predict dementia development. The question remains whether this association holds in the general population. This is of interest for the possible use of hippocampal atrophy to screen population for preventive interventions. The aim of this study was to assess hippocampal volume and shape abnormalities in elderly adults with memory deficits in a cross-sectional population-based study. Methods: We included individuals participating in the Italian Project on the Epidemiology of Alzheimer Disease (IPREA) study: 75 cognitively normal individuals (HC), 31 individuals with memory deficits (MEM), and 31 individuals with memory deficits not otherwise specified (MEMnos). Hippocampal volumes and shape were extracted through manual tracing and the growing and adaptive meshes (GAMEs) shape-modeling algorithm. We investigated between-group differences in hippocampal volume and shape, and correlations with memory deficits. Results: In MEM participants, hippocampal volumes were significantly smaller than in HC and were mildly associated with worse memory scores. Memory-associated shape changes mapped to the anterior hippocampus. Shape-based analysis detected no significant difference between MEM and HC, while MEMnos showed shape changes in the posterior hippocampus compared with HC and MEM groups. Conclusions: These findings support the discriminant validity of hippocampal volumetry as a biomarker of memory impairment in the general population. The detection of shape changes in MEMnos but not in MEM participants suggests that shape-based biomarkers might lack sensitivity to detect Alzheimer's-like pathology in the general population.

The Italian Alzheimer's Disease Neuroimaging Initiative (I-ADNI): Validation of Structural MR Imaging

Abstract: The North American Alzheimer's Disease Neuroimaging Initiative (NA-ADNI) was the first program to develop standardized procedures for Alzheimer's disease (AD) imaging biomarker collection. OBJECTIve: We describe the validation of acquisition and processing of structural magnetic resonance imaging (MRI) in different Italian academic AD clinics following NA-ADNI procedures.

Automatic temporal lobe atrophy assessment in prodromal AD: Data from the DESCRIPA study

Abstract: Background In the framework of the clinical validation of research tools, this investigation presents a validation study of an automatic medial temporal lobe atrophy measure that is applied to a naturalistic population sampled from memory clinic patients across Europe. Methods The procedure was developed on 1.5-T magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative database, and it was validated on an independent data set coming from the DESCRIPA study. All images underwent an automatic processing procedure to assess tissue atrophy that was targeted at the hippocampal region. For each subject, the procedure returns a classification index. Once provided with the clinical assessment at baseline and follow-up, subjects were grouped into cohorts to assess classification performance. Each cohort was divided into converters ( co ) and nonconverters ( nc ) depending on the clinical outcome at follow-up visit. Results We found the area under the receiver operating characteristic curve (AUC) was 0.81 for all co versus nc subjects, and AUC was 0.90 for subjective memory complaint (SMC nc ) versus all co subjects. Furthermore, when training on mild cognitive impairment (MCI -nc /MCI -co ), the classification performance generally exceeds that found when training on controls versus Alzheimer's disease (CTRL/AD). Conclusions Automatic magnetic resonance imaging analysis may assist clinical classification of subjects in a memory clinic setting even when images are not specifically acquired for automatic analysis.

Biomarker-based diagnosis of mild cognitive impairment due to Alzheimer's disease: how and what to tell. A kickstart to an ethical discussion.

Abstract: New criteria for the diagnosis of Alzheimer’s disease (AD) based on biomarker results have recently been developed and are currently undergoing extensive validation. The next few years may represent a time window where the diagnostic validity of biomarkers will be studied in highly specialized research settings. Biomarkers results will be used to direct clinical diagnosis and, whenever appropriate, therapy and management. This piece aims to stimulate discussion by identifying the ethical challenges involved in the use of biomarkers to make a diagnosis of mild cognitive impairment due to AD and disclose it to patients. At the individual level, these challenges are related to (i) the ethical appropriateness of implementing an ecological diagnostic research protocol, (ii) the related informed consent process, and (iii) the diagnostic disclosure. We justify the ethical legitimacy of implementing a research diagnostic protocol by referring to the respect of patients’ subjectivity and autonomy, and we suggest guidelines for informed consent development and diagnostic disclosure. All of the above points are discussed in light of the unique features of AD, currently scanty treatment options, and knowledge and uncertainties regarding the diagnostic value of biomarkers.

Electroencephalographic upper/low alpha frequency power ratio relates to cortex thinning in mild cognitive impairment.

Abstract: Objective: Temporoparietal cortex thinning is associated with mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase in EEG upper/low α frequ

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

Abstract: BACKGROUND:: Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS:: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid A?1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS:: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION:: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Rotigotine is safe and efficacious in Atypical Parkinsonism Syndromes induced by both α-synucleinopathy and tauopathy

Abstract: Transdermal rotigotine (RTG) is a non-ergot dopamine agonist (D3>D2>D1), and is indicated for use in early and advanced Parkinson’s disease (PD). RTG patch has many potential advantages due to the immediacy of onset of the therapeutic effect. Of note, intestinal absorption is not necessary and drug delivery is constant, thereby avoiding drug peaks and helping patient compliance. In turn, transdermal RTG seems a suitable candidate in the treatment of atypical Parkinsonian disorders (APS). Fifty-one subjects with a diagnosis of APS were treated with transdermal RTG. The diagnoses were: Parkinson’s disease with dementia, multiple system atrophy Parkinsonian type, multiple system atrophy cerebellar type, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, and frontotemporal dementia with Parkinsonism. Patients were evaluated by the Unified Parkinson’s Disease Rating Scale (UPDRS; part III), Neuropsychiatric Inventory (NPI), and mini–mental state examination (MMSE) and all adverse events (AEs) were recorded. Patients treated with RTG showed an overall decrease of UPDRS III scores without increasing behavioral disturbances. Main AEs were hypotension, nausea, vomiting, drowsiness, tachycardia, and dystonia. On the whole, 15 patients were affected by AEs and seven patients suspended RTG treatment due to AEs. The results show that transdermal RTG is effective with a good tolerability profile. RTG patch could be a good therapeutic tool in patients with APS.

Neural signatures of the interaction between the 5-HTTLPR genotype and stressful life events in healthy women

Abstract: A change in neural connectivity of brain structures implicated in the memory of negative life events has been hypothesized to explain the enhancement of memory encoding during the processing of negative stimuli in depressed patients. Here, we investigated the effects of the interaction between negative life events and the 5-HTTLPR genotype – a polymorphism of the serotonin transporter gene – on the functional and structural connectivity of the hippocampal area in 34 healthy women. All participants were genotyped for the presence of the 5-HTTLPR short variant and for the A/G single-nucleotide polymorphism; they underwent clinical assessment including structured diagnostic interviews to exclude the presence of psychiatric disorders and to assess the presence of stressful life events. Resting state functional magnetic resonance imaging and diffusion tensor imaging scans were performed. We found significant interactions between stressful events and the 5-HTTLPR genotype in both the functional connectivity of the parahippocampus with the posterior cingulate cortex and the structural connectivity between the hippocampus and both the amygdala and the putamen. In addition, we found several genotype-related differences in the relationship between functional/structural connectivity of the hippocampal area and the ability to update expectations or stress-related phenotypes, such as anxiety symptoms. If confirmed by future studies, these mechanisms may clarify the role of the 5HTTLPR genotype as a risk factor for depression, in interaction with negative events.

Determinants of Health and Disability in Ageing Population: The COURAGE in Europe Project (Collaborative Research on Ageing in Europe)

Abstract: UNLABELLED COURAGE in Europe was a 3-year project involving 12 partners from four European countries and the World Health Organization. It was inspired by the pressing need to integrate international studies on disability and ageing in light of an innovative perspective based on a validated data-collection protocol. COURAGE in Europe Project collected data on the determinants of health and disability in an ageing population, with specific tools for the evaluation of the role of the built environment and social networks on health, disability, quality of life and well-being. The main survey was conducted by partners in Finland, Poland and Spain where the survey has been administered to a sample of 10,800 persons, which was completed in March 2012. The newly developed and validated COURAGE Protocol for Ageing Studies has proven to be a valid tool for collecting comparable data in ageing population, and the COURAGE in Europe Project has created valid and reliable scientific evidence, demonstrating cross-country comparability, for disability and ageing research and policy development. It is therefore recommended that future studies exploring determinants of health and disability in ageing use the COURAGE-derived methodology. KEY PRACTITIONER MESSAGE COURAGE in Europe Project collected data on the determinants of health and disability in an ageing population, with specific tools for the evaluation of the role of built environment and social networks on health, disability quality of life and well-being. The COURAGE Protocol for Ageing Studies has proven to be a valid tool for collecting comparable data in the ageing population. The COURAGE in Europe Consortium recommends that future studies exploring determinants of health and disability in ageing use COURAGE-derived methodology.

The SIENA/FSL whole brain atrophy algorithm is no more reproducible at 3 T than 1.5 T for Alzheimer's disease

Abstract: The back-to-back (BTB) acquisition of MP-RAGE MRI scans of the Alzheimer׳s Disease Neuroimaging Initiative (ADNI1) provides an excellent data set with which to check the reproducibility of brain atrophy measures. As part of ADNI1, 131 subjects received BTB MP-RAGEs at multiple time points and two field strengths of 3T and 1.5 T. As a result, high quality data from 200 subject-visit-pairs was available to compare the reproducibility of brain atrophies measured with FSL/SIENA over 12 to 18 month intervals at both 3T and 1.5 T. Although several publications have reported on the differing performance of brain atrophy measures at 3T and 1.5 T, no formal comparison of reproducibility has been published to date. Another goal was to check whether tuning SIENA options, including -B, -S, -R and the fractional intensity threshold (f) had a significant impact on the reproducibility. The BTB reproducibility for SIENA was quantified by the 50th percentile of the absolute value of the difference in the percentage brain volume change (PBVC) for the BTB MP-RAGES. At both 3T and 1.5 T the SIENA option combination of "-B f=0.2", which is different from the default values of f=0.5, yielded the best reproducibility as measured by the 50th percentile yielding 0.28 (0.23-0.39)% and 0.26 (0.20-0.32)%. These results demonstrated that in general 3T had no advantage over 1.5 T for the whole brain atrophy measure - at least for SIENA. While 3T MRI is superior to 1.5 T for many types of measurements, and thus worth the additional cost, brain atrophy measurement does not seem to be one of them.

Behavioral and Neurophysiological Effects of Transdermal Rotigotine in Atypical Parkinsonism

Abstract: Effective therapies for the so-called atypical parkinsonian disorders (APS) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) are not available. Dopamine agonists are not often used in APS because of inefficacy and, in a minority of case, their side effects, like dyskinesias, impairment of extrapiramidal symptoms or the appearance of psychosis and REM sleep behavioral disorders. (RBD). Transdermal rotigotine (RTG) is a non-ergot dopamine agonist indicated for use in early and advanced Parkinson’s disease with a good tolerability and safety. Moreover, its action on a wide range of dopamine receptors, D1, D2, D3, unlike other dopamine agonists, could make it a good option in APS, where a massive dopamine cell loss is documented. In this pilot, observational open-label study we evaluate the efficacy and tolerability of RTG in patients affected by APS. 32 subjects with diagnosis of APS were treated with transdermal RTG. APS diagnosis was: multiple system atrophy parkinsonian type (MSA-P), multiple system atrophy cerebellar type (MSA-C), PSP, CBS. Patients were evaluated by UPDRS-III, NPI, MMSE at baseline and after 6, 12 and 18 months. The titration schedule was maintained very flexible, searching the major clinical effect and the minor possible adverse events at each visit. Adverse events were recorded. APS patients treated with RTG show a overall decrease of UPDRS III scores without increasing behavioral disturbances. Only 3 patients were dropped out of the study. Main adverse events were hypotension, nausea, vomiting, drowsiness, tachycardia. The EEG power spectra analysis shows a decrease of theta and an increase of low alpha power. In conclusion, transdermal RTG seems to be effective and well tolerated in APS patients.

Validation of the COURAGE Built Environment Self-Reported Questionnaire.

Abstract: The built environment (BE) impacts on people's disability and health, in terms of overweight, depression, alcohol abuse, poor self-rated health and presence of psychological symptoms; it is reasonable to assume that BE also impacts on participation levels. This paper presents the validation of the COURAGE Built Environment Self-Reported Questionnaire (CBE-SR), an instrument designed to evaluate BE in the context of health and disability. Subjects participating to COURAGE, a cross-sectional study conducted on 10 800 citizens of Poland, Finland and Spain, completed a protocol inclusive of the CBE-SR. Psychometric properties and factor structure were analysed, and factor scores created. Gender differences, differences between persons from different age groups and persons reporting the environment as facilitating, hindering or neutral were calculated. Eight items were deleted so that the final version of CBE-SR comprises 19 items. Cronbach's alpha ranged from 0.743 to 0.906, and test-retest stability was demonstrated for the majority of items. Four subscales were identified: Usability of the neighbourhood environment; Hindrance of walkable environment; Easiness of use of public buildings, places and facilities; and Risk of accidents and usability of the living place. Younger respondents reported their neighbourhood as more usable but perceived walkways as more hindering and public buildings as less easy to use; gender differences were almost inexistent. The CBE-SR is a four-scale instrument with good psychometric properties that measures the person-environment interaction. It is sensitive across age groups and is consistent with the subject's overall judgement of the degree to which the environment is facilitating or hindering. Copyright © 2013 John Wiley & Sons, Ltd. Key Practitioner Message Poor built environments have a negative impact on the level of a person's participation. However, instruments measuring the person-environment interaction are lacking.The CBE-SR is a valid and reliable instrument that researchers can use to assess the relationships between the intrinsic health state and the objective features of the environment. Understanding this relationship would provide further insight into the need of addressing the individual's functioning either by means of interventions directed to the individual or by making changes to the individual's environment. Language: en