Showing papers by "Giovanni B. Frisoni published in 2017"
TL;DR: The data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundances of an anti-inflammatoryTaxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis.
761 citations
TL;DR: This work sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice, indicating a microbial involvement in the development of Abeta amyloid pathology and suggesting that microbiota may contribute to the developed neurodegenerative diseases.
Abstract: Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.
544 citations
University of Geneva1, University of Gothenburg2, Sahlgrenska University Hospital3, VU University Amsterdam4, Istituto Universitario Di Studi Superiori Di Pavia5, Stockholm County Council6, University Hospital of Lausanne7, University of Zurich8, Lund University9, University of Manchester10, Mayo Clinic11, European Association of Nuclear Medicine12, University of Genoa13, Karolinska University Hospital14, Alzheimer's Association15, University of Amsterdam16, Vita-Salute San Raffaele University17, Queen Mary University of London18, Beta19, University of Bern20, University of Brescia21, Geneva College22, University of Malta23, Alzheimer Europe24, University College London25, Stanford University26, German Center for Neurodegenerative Diseases27, University of Rostock28, Imperial College London29, Maastricht University30, St. Jude Children's Research Hospital31, Karolinska Institutet32
TL;DR: A strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers is developed.
Abstract: The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
446 citations
TL;DR: Contrary to long-standing views, men and women with the APOE &egr;3/&egR;4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
Abstract: Importance It is unclear whether female carriers of the apolipoprotein E (APOE) e4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources Twenty-seven independent research studies in the Global Alzheimer’s Association Interactive Network with data on nearly 58 000 participants. Study Selection Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE e3/e4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE e3/e4 had an increased risk of AD compared with men with APOE e3/e3. The APOE e2/e3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more ( P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE e3/e4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE e4/e4 showed increased risks vs individuals with e3/e4, but no significant differences between men and women with e4/e4 were seen. Conclusions and Relevance Contrary to long-standing views, men and women with the APOE e3/e4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
410 citations
TL;DR: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses.
Abstract: The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170560. The study was sponsored by TauRx Therapeutics (Singapore). We thank Lon Schneider and Howard Feldman for their contribution to the Scientific Advisory Board. We gratefully acknowledge study investigators and the generosity of study participants. Authors’ disclosures available online (http://j-alz.com/manuscript disclosures/17-0560r3).
134 citations
University of Copenhagen1, University of Eastern Finland2, Karolinska University Hospital3, University of Coimbra4, University of Antwerp5, University of Gothenburg6, University of Geneva7, Polish Academy of Sciences8, Maastricht University9, Medical University of Białystok10, Beta11, Karolinska Institutet12, University of Ulm13, Turku University Hospital14, Hacettepe University15, Vanderbilt University Medical Center16, UCL Institute of Neurology17
TL;DR: There is sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia.
Abstract: This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β 1–42 , tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided
117 citations
University of Eastern Finland1, Copenhagen University Hospital2, Karolinska University Hospital3, University of Coimbra4, University of Antwerp5, University of Gothenburg6, University of Geneva7, Polish Academy of Sciences8, Maastricht University9, Medical University of Białystok10, Beta11, Karolinska Institutet12, University of Ulm13, Turku University Hospital14, Hacettepe University15, Vanderbilt University Medical Center16, UCL Institute of Neurology17
TL;DR: The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add‐on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management.
Abstract: This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β 1–42 , tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
107 citations
Maastricht University1, French Institute of Health and Medical Research2, Imperial College London3, Istituto Superiore di Sanità4, University of Geneva5, VU University Medical Center6, VU University Amsterdam7, Sahlgrenska University Hospital8, University of Gothenburg9, Dublin City University10, University of Glasgow11
TL;DR: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.
Abstract: Background: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual's prevention potential for dementia. Objective: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old. Methods: 9,387 non-demented individuals were recruited from the European population-based DESCRIPAstudy.An individual'sLIBRAindexwas calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1 16). Results: In midlife (55 69 y, n = 3,256) and late life (70 79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80 97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia. Conclusion: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.
88 citations
University of Antwerp1, Ghent University2, Autonomous University of Barcelona3, Technische Universität München4, Imperial College London5, Karolinska Institutet6, Karolinska University Hospital7, University of Brescia8, Sofia Medical University9, New Bulgarian University10, University of Lisbon11, University of Bonn12, University of Cologne13, German Center for Neurodegenerative Diseases14, Ludwig Maximilian University of Munich15, Katholieke Universiteit Leuven16, Cliniques Universitaires Saint-Luc17, University of Liège18, Carlos III Health Institute19, University of Barcelona20, University of Florence21, University of Coimbra22, University of Geneva23, University of Tübingen24, Charles University in Prague25, Medical University of Vienna26, University of Verona27
TL;DR: The mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum is investigated by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia, ALS, or FTD plus ALS ascertained within the European Early‐Onset Dementia Consortium.
Abstract: We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
81 citations
Sapienza University of Rome1, University of Naples Federico II2, University of Genoa3, University of London4, University of Chieti-Pescara5, University Hospital of Basel6, Johannes Kepler University of Linz7, Austrian Institute of Technology8, University of Geneva9, Istanbul Medipol University10, Istanbul University11, Dokuz Eylül University12, University of Foggia13
TL;DR: In quiet wakefulness, delta and alpha sources unveiled different spatial and frequency features of the cortical neural synchronization underpinning brain arousal in ADD, PDD, and DLB patients.
72 citations
University of Trento1, Harvard University2, University of Duisburg-Essen3, University of Göttingen4, University of Genoa5, Aix-Marseille University6, Lille University of Science and Technology7, French Institute of Health and Medical Research8, University of Toulouse9, University of Naples Federico II10, University of Perugia11, Interbalkan Medical Center12, University of Geneva13
TL;DR: This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes, and increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects.
Abstract: Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects. Hum Brain Mapp 38:12-26, 2017. © 2016 Wiley Periodicals, Inc.
UCL Institute of Neurology1, Erasmus University Rotterdam2, University of Brescia3, University of Milan4, Sunnybrook Health Sciences Centre5, University of Toronto6, University of Cambridge7, Karolinska University Hospital8, Laval University9, University of Western Ontario10, University of Lisbon11, University of Florence12, Karolinska Institutet13
TL;DR: Increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset.
TL;DR: Human longitudinal studies starting in the earlier disease phases are needed to understand the causative relation between microbiota and the hallmarks of these neurodegenerative disorders and to develop innovative treatments aimed at preventing or slowing brain damages.
Abstract: Purpose of reviewDespite the extensive research carried out in the past decades, the current pathophysiological notions of neurodegenerative disease as well as effective treatments to reduce their progression are largely unknown. Alterations of the human microbiota, the plethora of different microsc
TL;DR: A literature review of the clinical validity of amyloid positron emission tomography (PET) imaging using a structured framework developed for the assessment of oncological biomarkers concludes that there is adequate evidence that the main aims of phases 1 and 2 have been achieved.
TL;DR: The aim is to evaluate the evidence for use of medial temporal lobe atrophy as a biomarker for Alzheimer's disease at the mild cognitive impairment stage in routine clinical practice, with an adapted version of the 5-phase oncology framework for biomarker development.
Lund University1, VU University Medical Center2, Maastricht University3, Helen Wills Neuroscience Institute4, University of Antwerp5, Avid Radiopharmaceuticals6, Hospital de Sant Pau7, University of Geneva8, Université catholique de Louvain9, University of Caen Lower Normandy10, University of Texas at Dallas11, University of Erlangen-Nuremberg12, University of Gothenburg13, Jagiellonian University14, Post Graduate Institute of Medical Education and Research15, University Hospital of Lausanne16, Stavanger University Hospital17, Akershus University Hospital18, Leiden University Medical Center19, Pierre-and-Marie-Curie University20, University of Pittsburgh21, Technische Universität München22, University of Copenhagen23, Karolinska University Hospital24, Aristotle University of Thessaloniki25, Ludwig Maximilian University of Munich26, University of Eastern Finland27, The Catholic University of America28, New York University29, German Center for Neurodegenerative Diseases30, Linköping University31, Radboud University Nijmegen32, Washington University in St. Louis33, Medical University of Białystok34, University of Göttingen35, Heidelberg University36, Samsung Medical Center37, Carol Davila University of Medicine and Pharmacy38, Imperial College London39, University of Cologne40, Paris Descartes University41, University of Pennsylvania42, Eli Lilly and Company43, University of California, San Diego44, New Generation University College45, François Rabelais University46, Turku University Hospital47, Sahlgrenska University Hospital48, University of California, San Francisco49
TL;DR: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease, but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.
Abstract: Introduction: Apolipoprotein E (APOE) e4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE e4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE e4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE e4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
University of Cambridge1, University of Melbourne2, Sapienza University of Rome3, Mario Negri Institute for Pharmacological Research4, University of Barcelona5, Aix-Marseille University6, University of Perugia7, University of Duisburg-Essen8, University of Genoa9, Leipzig University10, University of Trento11, Centre national de la recherche scientifique12, Aristotle University of Thessaloniki13, University of Göttingen14, GlaxoSmithKline15, university of lille16, University of Geneva17
TL;DR: It is suggested that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.
TL;DR: Interestingly, this accuracy based on 8 (linear) rsEEG markers as inputs to ANN was similar to that obtained with a singlersEEG marker (Babiloni et al., 2016a), thus unveiling their information redundancy for classification purposes.
Abstract: Previous evidence showed a 75.5% best accuracy in the classification of 120 Alzheimer’s disease (AD) patients with dementia and 100 matched normal elderly (Nold) subjects based on cortical source current density and linear lagged connectivity estimated by eLORETA freeware from resting state eyes-closed electroencephalographic (rsEEG) rhythms (Babiloni et al., 2016). Specifically, that accuracy was reached using the ratio between occipital delta and alpha1 current density for a linear univariate classifier (receiver operating characteristic curves). Here we tested an innovative approach based on an artificial neural network (ANN) classifier from the same database of rsEEG markers. Frequency bands of interest were delta (2-4 Hz), theta (4-8 Hz Hz), alpha1 (8-10.5 Hz), and alpha2 (10.5-13 Hz). ANN classification showed an accuracy of 77% using the most 4 discriminative rsEEG markers of source current density (delta/alpha1 and theta/alpha1 ratios in posterior cortical lobes). It also showed an accuracy of 72% using the most 4 discriminative rsEEG markers of source lagged linear connectivity (alphas between posterior cortical lobes). With these 8 markers combined, an accuracy of at least 76% was reached. Although these linear rsEEG markers of cortical activity and connectivity unveil different relevant neurophysiological mechanisms underpinning cortical arousal and vigilance in AD patients, they provide quite redundant information for classification purposes. Future AD studies should use ANNs combining the present markers with other linear (i.e. directed transfer function) and nonlinear rsEEG markers to improve the classification accuracy.
Sapienza University of Rome1, University of Naples Federico II2, University of Genoa3, University of London4, University of Chieti-Pescara5, University Hospital of Basel6, Johannes Kepler University of Linz7, Austrian Institute of Technology8, University of Geneva9, Istanbul Medipol University10, Istanbul University11, Dokuz Eylül University12, University of Foggia13, Newcastle University14
TL;DR: Functional cortical connectivity markers in delta and alpha sources suggest a more compromised neurophysiological reserve in ADD than DLB, at both group and individual levels.
University of Brescia1, University of Pavia2, Erasmus University Rotterdam3, University of Milan4, Karolinska Institutet5, Karolinska University Hospital6, Sunnybrook Research Institute7, Toronto Western Hospital8, University of Cambridge9, Laval University10, University of Western Ontario11, University of Geneva12, University of Lisbon13, University of Florence14, UCL Institute of Neurology15
TL;DR: The effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD is explored, suggesting a possible strategy for delaying disease onset.
Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.
TL;DR: A methodological framework for their systematic validation, by reference to that developed for oncology biomarkers, is provided, to assess the current available evidence on the clinical validity of biomarkers for AD and to inform coordinated research efforts boosting AD biomarkers research.
Sapienza University of Rome1, University of Naples Federico II2, University of Genoa3, University of London4, University of Chieti-Pescara5, University Hospital of Basel6, Johannes Kepler University of Linz7, Austrian Institute of Technology8, Istanbul Medipol University9, Istanbul University10, Dokuz Eylül University11, University of Foggia12, University of Geneva13
TL;DR: The PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness.
Abstract: The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.
TL;DR: This article summarizes the workshop discussion of the Geneva Task Force "ethical and societal issues" working group, which comprised bioethicists, clinicians, health economists, and representatives of those affected by AD, and identified the following key issues that need to be included in the roadmap.
TL;DR: NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyriIn bvFTD for SN modulation.
Abstract: BACKGROUND The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design. OBJECTIVE Based on the observation that Alzheimer's disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits. METHODS A systematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method. RESULTS DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area - BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex. CONCLUSIONS NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation.
TL;DR: The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months and found knowledge of the amyloid status affects the diagnosis and alters patient management.
Abstract: Aims: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study. Methods: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months. Results: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit. Conclusion: Knowledge of the amyloid status affects the diagnosis and alters patient management.
UCL Institute of Neurology1, Montreal Neurological Institute and Hospital2, École Polytechnique Fédérale de Lausanne3, Siemens4, University Hospital of Lausanne5, University of Geneva6, University of Liège7, Dokuz Eylül University8, University of Antwerp9, Technische Universität München10, Ljubljana University Medical Centre11, Mercer University12, University of Perugia13, University of Genoa14, Aristotle University of Thessaloniki15, University of Coimbra16, Carol Davila University of Medicine and Pharmacy17, University of Belgrade18
TL;DR: In this article, an increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of −8.0% (95% credible interval: [−11.5, −5.6, −6.1], respectively).
Abstract: Introduction Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear. Methods Three hundred fifty-six patients, under clinical evaluation for cognitive impairment, with suspected AD and Mini–Mental State Examination ≥20, were recruited across 17 European memory clinics. After the traditional diagnostic workup, diagnostic confidence of AD pathology (DCAD) was estimated by the physicians in charge. The latter were provided with the results of automated hippocampal volumetry in standardized format and DCAD was reassessed. Results An increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of −8.0% (95% credible interval: [−11.5, −5.0]). Automated hippocampal volumetry showed a statistically significant impact on DCAD beyond the contributions of neuropsychology, 18 F-fluorodeoxyglucose positron emission tomography/single-photon emission computed tomography, and cerebrospinal fluid markers (−8.5, CrI: [−11.5, −5.6]; −14.1, CrI: [−19.3, −8.8]; −10.6, CrI: [−14.6, −6.1], respectively). Discussion There is a measurable effect of hippocampal volume on DCAD even when used on top of the traditional diagnostic workup.
Maastricht University1, Heidelberg University2, University of Erlangen-Nuremberg3, University of Göttingen4, University of Bonn5, Charité6, University of Antwerp7, Vrije Universiteit Brussel8, Aristotle University of Thessaloniki9, Karolinska Institutet10, Karolinska University Hospital11, Copenhagen University Hospital12, Katholieke Universiteit Leuven13, Catholic University of Leuven14, Hospital de Sant Pau15, University of Geneva16, University of Cologne17, Aix-Marseille University18, VU University Medical Center19, University of Liège20, University of Lisbon21, Hoffmann-La Roche22, Janssen Pharmaceutica23, Boehringer Ingelheim24, University of Eastern Finland25
TL;DR: It is suggested that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment, and only alcohol use increased the risk of cognitive decline, regardless of AD pathology.
TL;DR: The rationale and structure of the EDSD is described, the available data is summarized, and how to gain access to the database is explained.
Maastricht University1, University of Eastern Finland2, VTT Technical Research Centre of Finland3, Karolinska University Hospital4, Heidelberg University5, University of Genoa6, Radboud University Nijmegen7, Carol Davila University of Medicine and Pharmacy8, Aristotle University of Thessaloniki9, Lund University10, VU University Medical Center11
TL;DR: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.
Abstract: Background: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. Objective: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ 42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. Methods: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ 42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. Results: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. Conclusions: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.
TL;DR: There is an APOE ε4-dependent period of early alterations in amyloid homeostasis that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
Abstract: From earlier studies it is known that the APOE e2/e3/e4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1–42 (Aβ42) in patients with cognitive decline due to Alzheimer’s disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17–99 from nine different clinical research centers. CSF concentrations of Aβ42 were lower in APOE e4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE e4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE e4-negative individuals and 43 years in heterozygous APOE e4 carriers. Homozygous APOE e4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. People possessing the APOE e4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE e4 noncarriers already in early middle age. Homozygous APOE e4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE e4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.