Showing papers by "Giovanni B. Frisoni published in 2018"
University College London1, UCL Institute of Neurology2, King's College London3, Erasmus University Rotterdam4, University of Brescia5, University of Milan6, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico7, Sunnybrook Health Sciences Centre8, University of Toronto9, University of Cambridge10, Karolinska Institutet11, University of Geneva12, Laval University13, University of Western Ontario14, University of Lisbon15, University of Florence16
TL;DR: A machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies is introduced, using two neurodegenerative disease cohorts.
Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.
246 citations
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
TL;DR: Although there are important differences in atrophy patterns for each group, there are also similarities (a fronto-insula-anterior cingulate network) that help explain the clinical commonalities of the disease.
154 citations
Maastricht University1, VU University Medical Center2, Washington University in St. Louis3, Lund University4, University of Pittsburgh5, University of Geneva6, Eli Lilly and Company7, University of California, San Diego8, Hospital de Sant Pau9, Avid Radiopharmaceuticals10, University of Gothenburg11, University of Antwerp12, Samsung Medical Center13, French Institute of Health and Medical Research14, Helen Wills Neuroscience Institute15, University of Erlangen-Nuremberg16, Leipzig University17, University of Perugia18, University Hospital of Lausanne19, Akershus University Hospital20, New Generation University College21, The Catholic University of America22, National and Kapodistrian University of Athens23, Heidelberg University24, Université catholique de Louvain25, Polish Academy of Sciences26, Radboud University Nijmegen27, François Rabelais University28, Wrocław Medical University29, Imperial College London30, University of Cologne31, Turku University Hospital32, Thomas Jefferson University33, University of Lisbon34, University of Paris35, University of California, San Francisco36, Copenhagen University Hospital37, Ljubljana University Medical Centre38, Karolinska University Hospital39, Medical University of Białystok40, University of Pennsylvania41, Aristotle University of Thessaloniki42, Stavanger University Hospital43, Hoffmann-La Roche44, Sahlgrenska University Hospital45, Leiden University Medical Center46, Pierre-and-Marie-Curie University47, Technische Universität München48, University of Copenhagen49, Boehringer Ingelheim50, Ludwig Maximilian University of Munich51, University of Eastern Finland52, Jagiellonian University53, New York University54, German Center for Neurodegenerative Diseases55, Linköping University56, Janssen Pharmaceutica57, King's College London58, Charité59, University of Göttingen60, Carol Davila University of Medicine and Pharmacy61, UCL Institute of Neurology62
TL;DR: Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI and their value as a screening measure for early AD among persons without dementia is limited.
Abstract: Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
128 citations
Mercer University1, Trinity College, Dublin2, University College Dublin3, Tallaght Hospital4, King's College London5, university of lille6, University of Gothenburg7, Mario Negri Institute for Pharmacological Research8, University College Cork9, University of Ulm10, University of Szeged11, University of Limerick12, University of Southern California13, Maastricht University14, University of Milan15, University of Genoa16, Aristotle University of Thessaloniki17, Archer18, Roskamp Institute19
TL;DR: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease, and exploratory analyses of the planned secondary outcomes showed no substantial effects.
Abstract: BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
119 citations
TL;DR: The results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.
101 citations
TL;DR: It was generally concluded that FDG-PET has a diagnostic role in all scenarios and should be used for PICOs based on its negative predictive value and on the assistance it provides when typical patterns of hypometabolism for a given diagnosis are observed.
Abstract: To assess the clinical utility of FDG-PET as a diagnostic aid for differentiating Alzheimer’s disease (AD; both typical and atypical forms), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD), vascular dementia (VaD) and non-degenerative pseudodementia. A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted on six different diagnostic scenarios using the Delphi method. The level of empirical study evidence for the use of FDG-PET was considered good for the discrimination of DLB and AD; fair for discriminating FTLD from AD; poor for atypical AD; and lacking for discriminating DLB from FTLD, AD from VaD, and for pseudodementia. Delphi voting led to consensus in all scenarios within two iterations. Panellists supported the use of FDG-PET for all PICOs—including those where study evidence was poor or lacking—based on its negative predictive value and on the assistance it provides when typical patterns of hypometabolism for a given diagnosis are observed. Although there is an overall lack of evidence on which to base strong recommendations, it was generally concluded that FDG-PET has a diagnostic role in all scenarios. Prospective studies targeting diagnostically uncertain patients for assessing the added value of FDG-PET would be highly desirable.
76 citations
Maastricht University1, Katholieke Universiteit Leuven2, VU University Medical Center3, University of Antwerp4, University of Geneva5, Beta6, Geneva College7, University Hospital of Lausanne8, University of Oxford9, King's College London10, University of Lübeck11, Imperial College London12, University of Oslo13, Janssen Pharmaceutica14
TL;DR: The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of Aβ and APOE ε4 in AD pathogenesis.
Abstract: There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer’s disease (AD) in the predementia stages and to predict the rate of decline Therefore, we set up the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study In this report we describe the design of the study, the methods used and the characteristics of the participants Participants were selected from existing prospective multicenter and single-center European studies Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (Aβ) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA Visual rating and volumetric measures were assessed on MRI Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 679 (SD 83) years The percentage Aβ+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects For 759 (62%) individuals, clinical follow-up data were available In each diagnostic group, the APOE e4 allele was more frequent amongst Aβ+ individuals (p < 0001) Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p < 0001) Aβ+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0001) and MCI (p < 0001) groups The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of Aβ and APOE e4 in AD pathogenesis The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog
74 citations
TL;DR: FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD 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.
Abstract: 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. 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. 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. 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.
56 citations
VU University Medical Center1, Maastricht University2, Katholieke Universiteit Leuven3, GlaxoSmithKline4, university of lille5, University of Gothenburg6, Beta7, University of Antwerp8, University Hospital of Lausanne9, Geneva College10, Aristotle University of Thessaloniki11, University of Oxford12, King's College London13, Imperial College London14, University of Oslo15, University of Lübeck16, Janssen Pharmaceutica17, Boehringer Ingelheim18, Pfizer19, Vanderbilt University Medical Center20, University of Geneva21
TL;DR: An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy and could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.
Abstract: 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) e4 genotype, can be used to predict amyloid pathology using machine-learning classification. 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 e4 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. 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 e4, 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 e4 information did not improve after additionally adding imaging measures. Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE e4 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.
55 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, Newcastle University14
TL;DR: The ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness.
Abstract: The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 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) score was matched between the ADMCI and DLBMCI 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 (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI 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 the clinical validity of these rsEEG markers.
47 citations
Sapienza University of Rome1, University of Naples Federico II2, University of Genoa3, University of Chieti-Pescara4, University Hospital of Basel5, Johannes Kepler University of Linz6, Austrian Institute of Technology7, Istanbul Medipol University8, Istanbul University9, Dokuz Eylül University10, University of Foggia11, Newcastle University12, University of Geneva13
TL;DR: These findings unveil similar abnormalities in functional cortical connectivity estimated in widespread alpha sources in ADMCI and PDMCI, true at both group and individual levels.
TL;DR: TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis, based on the assessment of intracortical connectivity with TMS.
Abstract: Background Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia. Objective To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI). Methods A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed. Results We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%. Conclusions The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.
University College London1, Erasmus University Rotterdam2, Leiden University Medical Center3, University of London4, Leiden University5, University of Brescia6, University of Milan7, Sunnybrook Research Institute8, University of Toronto9, University of Cambridge10, Karolinska University Hospital11, University of Geneva12, Laval University13, University of Western Ontario14, University of Lisbon15, University of Florence16
TL;DR: This work aimed to investigate mutation‐specific white matter integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT, and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study.
Abstract: Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72, MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers. Results: Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC. Interpretation: This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network-based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease-tracking and -staging in presymptomatic to early-stage familial FTD.
Laval University1, UCL Institute of Neurology2, Sunnybrook Health Sciences Centre3, Erasmus University Rotterdam4, University of Brescia5, University of Milan6, University of Toronto7, University of Cambridge8, Karolinska University Hospital9, Karolinska Institutet10, University of Lisbon11, University of Florence12
TL;DR: The findings support overlapping brain structural changes between FTD and primary psychiatric disorders, and appear to be distinct across the main forms of genetic FTD.
Abstract: Background:
The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations. //
Objective:
We aimed to identify whether NPS could be driven by distinct structural correlates. //
Methods:
One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. //
Results:
Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. //
Conclusion:
Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.
TL;DR: There is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE ε4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD.
Abstract: Purpose: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer’s disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) e4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. Methods: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. Results: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE e4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. Conclusion: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE e4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications.
TL;DR: Data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.
Abstract: The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.
University of Florence1, University of Milan2, UCL Institute of Neurology3, Erasmus University Rotterdam4, University of Brescia5, University of Lisbon6, Sunnybrook Health Sciences Centre7, University of Toronto8, University of Cambridge9, Karolinska Institutet10, Karolinska University Hospital11, Laval University12, University of Western Ontario13
TL;DR: These simple-to-use and reproducible visual rating scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.
Abstract: In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms. Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas). Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers. These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.
TL;DR: This review will summarize NIBS results in the context of brain imaging studies of functional connectivity and metabolites to gain insight into the possible mechanisms underlying recovery and review studies combining magnetic resonance spectroscopy and NIBS to investigate how microscale changes are related to modifications of large-scale networks.
Abstract: Non-invasive brain stimulation (NIBS) is emerging as a promising rehabilitation tool for a number of neurodegenerative diseases. However, the therapeutic mechanisms of NIBS are not completely understood. In this review, we will summarize NIBS results in the context of brain imaging studies of functional connectivity and metabolites to gain insight into the possible mechanisms underlying recovery. We will briefly discuss how the clinical manifestations of common neurodegenerative disorders may be related with aberrant connectivity within large-scale neural networks. We will then focus on recent studies combining resting-state functional magnetic resonance imaging with NIBS to delineate how stimulation of different brain regions induce complex network modifications, both at the local and distal level. Moreover, we will review studies combining magnetic resonance spectroscopy and NIBS to investigate how microscale changes are related to modifications of large-scale networks. Finally, we will re-examine previous NIBS studies in dementia in light of this network perspective. A better understanding of NIBS impact on the functionality of large-scale brain networks may be useful to design beneficial treatments for neurodegenerative disorders.
VU University Medical Center1, University of Leicester2, University of Geneva3, Geneva College4, Emory University5, University of Lausanne6, Karolinska Institutet7, University of Eastern Finland8, National Institutes of Health9, Pompeu Fabra University10, University of Edinburgh11, University of Montpellier12, French Institute of Health and Medical Research13, Pfizer14, Maastricht University15
TL;DR: The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies as mentioned in this paper, which is a virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohorts.
Abstract: Introduction It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. Methods A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. Results To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. Discussion This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies.
University of Antwerp1, Katholieke Universiteit Leuven2, Université catholique de Louvain3, Ghent University4, University of Brescia5, Carlos III Health Institute6, University of Lisbon7, University of Florence8, University of Coimbra9, Autonomous University of Barcelona10, University of Geneva11, University of Barcelona12
TL;DR: Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients, establishing SORT1 as a genetic risk factor for FTD.
TL;DR: An incremental diagnostic value of FDG-PET versus clinical diagnosis or lack thereof cannot be derived from the current literature, and many of the observed limitations may easily be overcome and are outlined as research priorities to improve the quality of current evidence.
Abstract: Background: FDG-PET is frequently used as a marker of synaptic damage to diagnose dementing neurodegenerative disorders. We aimed to adapt the items of evidence quality to FDG-PET diagnostic studies, and assess the evidence available in current literature to assist Delphi decisions for European recommendations for clinical use. Methods: Based on acknowledged methodological guidance, we defined the domains, specific to FDG-PET, required to assess the quality of evidence in 21 literature searches addressing as many Population Intervention Comparison Outcome (PICO) questions. We ranked findings for each PICO and fed experts making Delphi decisions for recommending clinical use. Results: Among the 1435 retrieved studies, most lacked validated measures of test performance, an adequate gold standard, and head-to-head comparison of FDG-PET and clinical diagnosis, and only 58 entered detailed assessment. Only two studies assessed the accuracy of the comparator (clinical diagnosis) versus any kind of gold−/reference-standard. As to the index-test (FDG-PET-based diagnosis), an independent gold-standard was available in 24% of the examined papers; 38% used an acceptable reference-standard (clinical follow-up); and 38% compared FDG-PET-based diagnosis only to baseline clinical diagnosis. These methodological limitations did not allow for deriving recommendations from evidence. Discussion: An incremental diagnostic value of FDG-PET versus clinical diagnosis or lack thereof cannot be derived from the current literature. Many of the observed limitations may easily be overcome, and we outlined them as research priorities to improve the quality of current evidence. Such improvement is necessary to outline evidence-based guidelines. The available data were anyway provided to expert clinicians who defined interim recommendations.
TL;DR: It is tested the hypothesis that amyloid–positron emission tomography prescriptions, considered appropriate based on the Amyloid Imaging Taskforce (AIT) criteria, lead to greater clinical utility than AIT‐inappropriate prescriptions.
Abstract: Introduction We test the hypothesis that amyloid–positron emission tomography prescriptions, considered appropriate based on the Amyloid Imaging Taskforce (AIT) criteria, lead to greater clinical utility than AIT-inappropriate prescriptions. Methods We compared the clinical utility between patients who underwent amyloid–positron emission tomography appropriately or inappropriately and among the subgroups of patients defined by the AIT criteria. Finally, we performed logistic regressions to identify variables associated with clinical utility. Results We identified 171 AIT-appropriate and 67 AIT-inappropriate patients. AIT-appropriate and AIT-inappropriate cases did not differ in any outcomes of clinical utility (P > .05). Subgroup analysis denoted both expected and unexpected results. The logistic regressions outlined the primary role of clinical picture and clinical or neuropsychological profile in identifying patients benefitting from amyloid–positron emission tomography. Discussion Contrary to our hypothesis, also AIT-inappropriate prescriptions were associated with clinical utility. Clinical or neuropsychological variables, not taken into account by the AIT criteria, may help further refine criteria for appropriateness.
TL;DR: Based on this preliminary investigation, delirium pathophysiology might be independent of Alzheimer's disease, and future studies on larger samples are needed to confirm this hypothesis.
TL;DR: The results suggest that early AD affects cortical neural synchronization at alpha frequencies underpinning brain arousal and low vigilance in the quiet wakefulness, in contrast to CKD, which may principally affect cortical Neural synchronization at the delta frequencies.
Abstract: This study tested whether resting state alpha rhythms (8-13 Hz) may characterize mild cognitive impairment due to Alzheimer's disease (ADMCI) compared with MCI due to chronic kidney disease (CKDMCI). Clinical and resting state eyes-closed electroencephalographic (rsEEG) rhythms from 40 ADMCI, 29 CKDMCI, and 45 cognitively normal elderly (Nold) subjects were available in a national archive. Age, gender, and education were matched in the three groups, and Mini-Mental State Evaluation (MMSE) score was paired in the ADMCI and CKDMCI groups. Delta (<4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz) cortical sources were estimated by eLORETA freeware and classified across individuals by area under the receiver operating characteristic curve (AUROCC). Compared with Nold group, posterior alpha 1 source activities were more reduced in ADMCI than CKDMCI group. In contrast, widespread delta source activities were greater in CKDMCI than ADMCI group. These source activities correlated with the MMSE score and correctly classified between Nold and all MCI individuals (AUROCC = 0.8-0.85) and between ADMCI and CKDMCI subjects (AUROCC = 0.75). These results suggest that early AD affects cortical neural synchronization at alpha frequencies underpinning brain arousal and low vigilance in the quiet wakefulness. In contrast, CKD may principally affect cortical neural synchronization at the delta frequencies. Future prospective cross-validation studies will have to test these candidate rsEEG markers for clinical applications and drug discovery.
TL;DR: The clinical protocols and practical details of FDG, amyloid, and tau PET/MR imaging as applied in institutions are covered.
Abstract: Multiple factors, namely amyloid, tau, inflammation, metabolic, and perfusion changes, contribute to the cascade of neurodegeneration and functional decline occurring in Alzheimer's disease (AD). These molecular and cellular processes and related functional and morphological changes can be visualized in vivo by two imaging modalities, namely positron emission tomography (PET) and magnetic resonance imaging (MRI). These imaging biomarkers are now part of the diagnostic algorithm and of particular interest for patient stratification and targeted drug development.In this field the availability of hybrid PET/MR systems not only offers a comprehensive evaluation in a single imaging session, but also opens new possibilities for the integration of the two imaging information. Here, we cover the clinical protocols and practical details of FDG, amyloid, and tau PET/MR imaging as applied in our institutions.
TL;DR: The data show that education, as a proxy of reserve, is not a major confounder in the diagnostic accuracy of FDG-PET in AD and the adoption of education-adjusted thresholds is not required in daily practice.
Abstract: Background A corollary of the reserve hypothesis is that what is regarded as pathological cortical metabolism in patients might vary according to education. Objective The aim of this study is to assess the incremental diagnostic value of education-adjusted over unadjusted thresholds on the diagnostic accuracy of FDG-PET as a biomarker for Alzheimer disease (AD). Methods We compared cortical metabolism in 90 healthy controls and 181 AD patients from the Alzheimer Disease Neuroimaging Initiative (ADNI) database. The AUC of the ROC curve did not differ significantly between the whole group and the higher-education patients or the lower-education subjects. Results The threshold of wMetaROI values providing 80% sensitivity was lower in higher-education patients and higher in the lower-education patients, compared to the standard threshold derived over the whole AD collective, without, however, significant changes in sensitivity and specificity. Conclusion These data show that education, as a proxy of reserve, is not a major confounder in the diagnostic accuracy of FDG-PET in AD and the adoption of education-adjusted thresholds is not required in daily practice.
TL;DR: Preliminary results of this study suggest high volume reproducibility for the different hippocampal subfields and the whole hippocampus, and generally better than those of other published studies, where no FLAIR and high-resolution T2 images were used.
VU University Medical Center1, University of Leicester2, University of Geneva3, Emory University4, University of Lausanne5, Geneva College6, National Institutes of Health7, University of Eastern Finland8, Karolinska Institutet9, Pompeu Fabra University10, University of Edinburgh11, French Institute of Health and Medical Research12, University of Montpellier13, Pfizer14, Maastricht University15
TL;DR: The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies by introducing a novel approach to find participants for AD prevention trials.
Abstract: Introduction It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. Methods A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. Results To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. Discussion This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies.
TL;DR: Post-mortem validations of in vivo data in large cohorts and studies investigating the clinical added value of this biomarker in comparison with others will be required before routine clinical use of this new modality.
Abstract: The development and validation of molecular imaging markers for the neuropathological hallmarks of neurodegenerative diseases associated with cognitive impairment is a reality since two decades. Amyloid PET tracers have been validated analytically and are currently tested for their clinical utility. More recently tracers targeting specifically tau deposits have been developed and are currently tested in large clinical studies. The availability of these markers opens the possibility for precision medicine in a field that was limited by a gold standard diagnosis occurring only postmortem. Aim of this review is to summarize the main findings obtained using tau-specific PET tracers in clinical cohorts of patients with cognitive impairment. We report the results of a systematic literature review. Various approaches for automated image assessment have been tested, while visual rating strategies have not been validated yet. In the AD spectrum an increase in cortical binding has been consistently observed, with a topography correlated with the profile of cognitive impairment and in agreement with the knowledge on tau pathology from neuropathological series. The evidence in non-AD diseases is more limited, with discordant findings in different cohorts and with different tracers. Post-mortem validations of in vivo data in large cohorts and studies investigating the clinical added value of this biomarker in comparison with others will be required before routine clinical use of this new modality.