Showing papers by "Giovanni B. Frisoni published in 2015"
University College London1, University of London2, Erasmus University Rotterdam3, Leiden University Medical Center4, Sunnybrook Health Sciences Centre5, University of Toronto6, University Health Network7, Laval University8, University of Brescia9, University of Milan10, University of Cambridge11, Karolinska Institutet12, Karolinska University Hospital13, University of Geneva14, University of Western Ontario15, University of Florence16
TL;DR: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia, which could help to define biomarkers that can stage presymPTomatic disease and track disease progression.
Abstract: Summary Background Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin ( GRN ), microtubule-associated protein tau ( MAPT ), or chromosome 9 open reading frame 72 ( C9orf72 ). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT , or C9orf72 , or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test −0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all −0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference −0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference −0·2, SE 0·1). Interpretation Structural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding Centres of Excellence in Neurodegeneration.
448 citations
Maastricht University1, Heidelberg University2, University of Erlangen-Nuremberg3, University of Göttingen4, University of Bonn5, Charité6, University of Genoa7, University of Geneva8, University of Cologne9, Aix-Marseille University10, VU University Amsterdam11, King's College London12, University of Eastern Finland13, Medical University of Łódź14, University of Perugia15, Aristotle University of Thessaloniki16, French Institute of Health and Medical Research17, University of Oxford18, University of Brescia19, University of Liège20, University of Gothenburg21, University of Lisbon22, University of Coimbra23, University of Antwerp24, Karolinska University Hospital25, Lund University26, Pierre-and-Marie-Curie University27, VU University Medical Center28
TL;DR: The use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage and the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis are supported.
Abstract: Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
279 citations
German Center for Neurodegenerative Diseases1, University of Rostock2, University of Cologne3, Leipzig University4, University of Caen Lower Normandy5, United States Department of Veterans Affairs6, Hartford Hospital7, Yale University8, Pierre-and-Marie-Curie University9, University of Geneva10, University of Greifswald11, University of East Anglia12, University of Utah13
TL;DR: The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.
Abstract: Alzheimer's disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimer's disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimer's disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimer's disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.
220 citations
University of Geneva1, Mayo Clinic2, University of Brescia3, Boston University4, University of Eastern Finland5, Oregon Health & Science University6, UCL Institute of Neurology7, German Center for Neurodegenerative Diseases8, University of California, Davis9, Utrecht University10, Rush University11, University of California, Los Angeles12, Laval University13, University of Mainz14, Semel Institute for Neuroscience and Human Behavior15, Northwestern University16, Newcastle University17, VU University Amsterdam18, University of Rostock19, Karolinska Institutet20, VU University Medical Center21, University of Alberta22, McGill University23, University of Zurich24, New York University25, Goethe University Frankfurt26
TL;DR: In this article, a harmonized protocol (HarP) was defined for the manual segmentation of the hippocampus on MR images and the results showed that the HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers.
Abstract: Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P P Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
165 citations
University of Brescia1, University of California, Los Angeles2, UCL Institute of Neurology3, University of California, Davis4, Rush University5, Newcastle University6, VU University Medical Center7, Boston University8, University of Alberta9, McGill University10, Laval University11, University of Eastern Finland12, Northwestern University13, Wayne State University14, University of Zurich15, German Center for Neurodegenerative Diseases16, Mayo Clinic17, University of Geneva18
TL;DR: In this paper, the authors aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.
Abstract: Background This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation. Methods The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. Results Agreement was significant on the inclusion of alveus/fimbria ( P = .021), whole hippocampal tail ( P = .013), medial border of the body according to visible morphology ( P = .0006), and on this combined set of features ( P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates. Discussion Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.
134 citations
TL;DR: The notion that patients with SNAP MCI feature a specific risk progression profile is supported, and lower time to progression was correlated with greater hypometabolism and hippocampal atrophy was more severe in SNAP patients.
Abstract: Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non–Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods: We measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [ 18 F]-fluorodeoxyglucose–PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A− and N+/N− based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A−N+ cases. Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A−N−, A+N−, SNAP, and A+N+, respectively; the proportion of APOE e4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N− and A+N+ groups ( p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients ( p = 0.154), while hippocampal atrophy was more severe in SNAP patients ( p = 0.002). Compared with A−N−, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p p = 0.771). In A+N− and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism ( r = 0.42, p = 0.073). Conclusions: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.
120 citations
TL;DR: This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms.
Abstract: Background The European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms. Methods Sixty-eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction. Results Hippocampal volumes (mm 3 ) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer's disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = P = Cerebrospinal fluid spaces (mm 3 ) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy. Conclusions This work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.
116 citations
University of Pennsylvania1, University of Gothenburg2, UCL Institute of Neurology3, VU University Amsterdam4, New York University5, Università degli Studi eCampus6, Lund University7, University of Antwerp8, Pierre-and-Marie-Curie University9, Johns Hopkins University School of Medicine10, Emory University11, Harvard University12, University of Geneva13
TL;DR: APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
Abstract: In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE e4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE e2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
110 citations
TL;DR: The results suggest that the amplitude of occipital sources of resting-state alpha rhythms is related to AD neurodegeneration in Occipital lobe along pathologic aging.
94 citations
TL;DR: Functional magnetic resonance imaging studies have shown that APOE ε2‐ and ε4‐carriers have similar patterns of blood‐oxygenation‐level‐dependent (BOLD) activation suggesting that the authors need to look beyond the BOLD signal to link APOE's effect on the brain to Alzheimer's disease (AD)‐risk.
Abstract: Background Functional magnetic resonance imaging (MRI) studies have shown that APOE e2- and e4-carriers have similar patterns of blood-oxygenation-level-dependent (BOLD) activation suggesting that we need to look beyond the BOLD signal to link APOE' s effect on the brain to Alzheimer's disease (AD)-risk. Methods We evaluated APOE -related differences in BOLD activation in response to a memory task, cerebrovascular reactivity using a CO 2 -inhalation challenge (CO 2 -CVR), and the potential contribution of CO 2 -CVR to the BOLD signal. Results APOE e4-carriers had the highest task-related hippocampal BOLD signal relative to non-carriers. The largest differences in CO 2 -CVR were between e2- and e4-carriers, with the latter having the lowest values. Genotype differences in CO 2 -CVR accounted for ∼70% of hippocampal BOLD differences between groups. Conclusion Because CO 2 -CVR gauges vascular health, the differential effect of APOE in young adults may reflect a vascular contribution to the vulnerability of e4-carriers to late-life pathology. Studies confirming our findings are warranted.
86 citations
TL;DR: Assessment of the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls found high accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier applied on predefined anatomo-functional regions and inter-hemispheric asymmetries.
TL;DR: This work aims to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients.
Abstract: Introduction Proposed diagnostic criteria (international working group and National Institute on Aging and Alzheimer's Association) for Alzheimer's disease (AD) include markers of amyloidosis (abnormal cerebrospinal fluid [CSF] amyloid beta [Aβ]42) and neurodegeneration (hippocampal atrophy, temporo-parietal hypometabolism on [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and abnormal CSF tau). We aim to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients. Methods In 73 MCI patients, followed to ascertain AD progression, markers were measured. Sensitivity and specificity, positive (LR+) and negative (LR−) likelihood ratios, and crude and adjusted hazard ratios were computed. Results Twenty-nine MCI patients progressed and 44 remained stable. Positivity to any marker achieved the lowest LR− (0.0), whereas the combination Aβ42 plus FDG-PET achieved the highest LR+ (6.45). In a survival analysis, positivity to any marker was associated with 100% conversion rate, whereas negativity to all markers was associated with 100% stability. Discussion The best criteria combined amyloidosis and neurodegeneration biomarkers, whereas the individual biomarker with the best performance was FDG-PET.
University College London1, UCL Institute of Neurology2, Bahçeşehir University3, Commonwealth Scientific and Industrial Research Organisation4, Harvard University5, French Institute for Research in Computer Science and Automation6, Mayo Clinic7, Montreal Neurological Institute and Hospital8, IBM9, University of Pennsylvania10
TL;DR: Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity, and there were large and statistically significant differences in the sample size requirements between many of the techniques.
TL;DR: Investigating the accuracy of FDG-PET to detect the Alzheimer's disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls found an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity.
Abstract: We aimed to investigate the accuracy of FDG-PET to detect the Alzheimer's disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls. aMCI patients were followed for at least two years or until conversion to dementia. Images were evaluated by means of visual read by either moderately-skilled or expert readers, and by means of a summary metric of AD-like hypometabolism (PALZ score). Seventy-seven patients converted to AD-dementia after 28.6 ± 19.3 months of follow-up. Expert reading was the most accurate tool to detect these MCI converters from healthy controls (sensitivity 89.6%, specificity 89.0%, accuracy 89.2%) while two moderately-skilled readers were less (p < 0.05) specific (sensitivity 85.7%, specificity 79.8%, accuracy 82.3%) and PALZ score was less (p < 0.001) sensitive (sensitivity 62.3%, specificity 91.7%, accuracy 79.6%). Among the remaining 67 aMCI patients, 50 were confirmed as aMCI after an average of 42.3 months, 12 developed other dementia, and 3 reverted to normalcy. In 30/50 persistent MCI patients, the expert recognized the AD hypometabolic pattern. In 13/50 aMCI, both the expert and PALZ score were negative while in 7/50, only the PALZ score was positive due to sparse hypometabolic clusters mainly in frontal lobes. Visual FDG-PET reads by an expert is the most accurate method but an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity, and should be mandatory when even a moderately-skilled reader is unavailable.
Laval University1, Mayo Clinic2, University of Geneva3, University of California, Los Angeles4, Northwestern University5, New York University6, Rush University Medical Center7, Boston University8, Pierre-and-Marie-Curie University9, University of Alberta10, Goethe University Frankfurt11, McGill University12, University of Eastern Finland13, Detroit Receiving Hospital14
TL;DR: Hippocampal volumetry on magnetic resonance imaging is recognized as an Alzheimer's disease biomarker, and manual segmentation is the gold standard for measurement.
Abstract: Background Hippocampal volumetry on magnetic resonance imaging is recognized as an Alzheimer's disease (AD) biomarker, and manual segmentation is the gold standard for measurement. However, a standard procedure is lacking. We operationalize and quantitate landmark differences to help a Delphi panel converge on a set of landmarks. Methods One hundred percent of anatomic landmark variability across 12 different protocols for manual segmentation was reduced into four segmentation units (the minimum hippocampus, the alveus/fimbria, the tail, and the subiculum), which were segmented on magnetic resonance images by expert raters to estimate reliability and AD-related atrophy. Results Intra- and interrater reliability were more than 0.96 and 0.92, respectively, except for the alveus/fimbria, which were 0.86 and 0.77, respectively. Of all AD-related atrophy, the minimum hippocampus contributed to 67%; tail, 24%; alveus/fimbria, 4%; and the subiculum, 5%. Conclusions Anatomic landmark variability in available protocols can be reduced to four discrete and measurable segmentation units. Their quantitative assessment will help a Delphi panel to define a set of landmarks for a harmonized protocol.
TL;DR: AD is characterized by localized disease-specific brain changes as well as by an accelerated global aging process, and this method may represent a more precise instrument to identify potential clinical outcomes in clinical trials for disease modifying drugs.
University of California, Los Angeles1, San Francisco State University2, Yale University3, University of Rochester4, University of Brescia5, Mayo Clinic6, University of Geneva7, Northwestern University8, New York University9, Rush University Medical Center10, Boston University11, University of Paris12, University of Alberta13, Goethe University Frankfurt14, McGill University15, University of Eastern Finland16, Detroit Receiving Hospital17
TL;DR: The pathologic validation of European Alzheimer's Disease Consortium Alzheimer’s Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP) is presented.
Abstract: Objective The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP). Methods Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained. Results We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = −0.75, P = .001), tau (ρ = −0.53, P = .034), Aβ burden (ρ = −0.61, P = .012), and neuronal count (ρ = 0.77, P P = .019) and subiculum (ρ = −0.75, P = .001), tau in CA2 (ρ = −0.59, P = .016), and CA3 (ρ = −0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001). Conclusions The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.
University of Brescia1, University of Bristol2, Catholic University of the Sacred Heart3, Aix-Marseille University4, Karolinska Institutet5, Heidelberg University6, Leipzig University7, University of Eastern Finland8, University Hospital Bonn9, University of Bonn10, Royal United Hospital11, Mercer University12, University of Perugia13, University of Basel14, University of Genoa15, Radboud University Nijmegen16, Lille University of Science and Technology17, Charité18, University of Liège19, University of Coimbra20, Paris Descartes University21, Aristotle University of Thessaloniki22, VU University Amsterdam23, Maastricht University24, Lund University25, John Radcliffe Hospital26, Moorgreen Hospital27, Dokuz Eylül University28, University of Geneva29
TL;DR: Responses largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature, and felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD.
Abstract: We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI) We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau) The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%) Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate" Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < 02 versus any individual biomarker) Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature
TL;DR: Patients with bvFTD patients had lower hypothalamic volumes compared with controls, and different genetic mutations may have a differential impact on the hypothalamus.
Abstract: Abnormal eating behaviors are frequently reported in behavioral variant frontotemporal dementia (bvFTD). The hypothalamus is the regulatory center for feeding and satiety but its involvement in bvFTD has not been fully clarified, partly due to its difficult identification on MR images. We measured hypothalamic volume in 18 patients with bvFTD (including 9 MAPT and 6 C9orf72 mutation carriers) and 18 cognitively normal controls using a novel optimized multimodal segmentation protocol, combining 3D T1 and T2-weighted 3T MRIs (intrarater intraclass correlation coefficients C0.93). The whole hypothalamus was subsequently segmented into five sub- units: the anterior (superior and inferior), tuberal (superior and inferior), and posterior regions. The presence of abnormal eating behavior was assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). The bvFTD group showed a 17 % lower hypothalamic volume compared with controls (p\0.001): mean 783 (standard deviation 113) versus 944 (73) mm 3 (corrected for total intracranial volume). In the hypothalamic subunit analysis, the superior parts of the anterior and tuberal regions and the posterior region were significantly smaller in the bvFTD group compared with controls. There was a trend for a smaller hypothalamic volume, particularly in the superior tuberal region, in those with severe eating disturbance scores on the CBI-R. Differences were seen between the two genetic subgroups with significantly smaller volumes in the MAPT but not the C9orf72 group compared with controls. In summary, bvFTD patients had lower hypothalamic volumes compared with controls. Different genetic mutations may have a differential impact on the hypothalamus.
University of Brescia1, Laval University2, University of California, Los Angeles3, Mayo Clinic4, University of Mainz5, University of Geneva6, University of California, Davis7, Rush University Medical Center8, Newcastle University9, Karolinska Institutet10, VU University Amsterdam11, Boston University12, University of Alberta13, McGill University14, University of Eastern Finland15, Northwestern University16
TL;DR: The aim was to produce benchmark labels based on the HarP for manual segmentation based on magnetic resonance for Alzheimer's Disease Neuroimaging Initiative benchmark labels.
Abstract: Background A globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation. Methods Five experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.5 T and 3 T scans. An independent expert visually checked segmentations for compliance with the HarP. Descriptive measures of agreement between tracers were intraclass correlation coefficients (ICCs) of crude volumes and similarity coefficients of three-dimensional volumes. Results Two hundred labels have been provided for the 20 magnetic resonance images. Intra- and interrater ICCs were >0.94, and mean similarity coefficients were 1.5 T, 0.73 (95% confidence interval [CI], 0.71–0.75); 3 T, 0.75 (95% CI, 0.74–0.76). Conclusion Certified benchmark labels have been produced based on the HarP to be used for tracers' training and qualification.
TL;DR: The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials by setting a new standard for data sharing without embargo.
Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.
TL;DR: Civet appears slightly more sensitive to the typical AD atrophic pattern at the MCI stage, but both pipelines can accurately characterize the topography of cortical thinning at the dementia stage.
Abstract: Background and Purpose
The measurement of cortical shrinkage is a candidate marker of disease progression in Alzheimer’s. This study evaluated the performance of two pipelines: Civet-CLASP (v1.1.9) and Freesurfer (v5.3.0).
Methods
Images from 185 ADNI1 cases (69 elderly controls (CTR), 37 stable MCI (sMCI), 27 progressive MCI (pMCI), and 52 Alzheimer (AD) patients) scanned at baseline, month 12, and month 24 were processed using the two pipelines and two interconnected e-infrastructures: neuGRID (https://neugrid4you.eu) and VIP (http://vip.creatis.insa-lyon.fr). The vertex-by-vertex cross-algorithm comparison was made possible applying the 3D gradient vector flow (GVF) and closest point search (CPS) techniques.
Results
The cortical thickness measured with Freesurfer was systematically lower by one third if compared to Civet’s. Cross-sectionally, Freesurfer’s effect size was significantly different in the posterior division of the temporal fusiform cortex. Both pipelines were weakly or mildly correlated with the Mini Mental State Examination score (MMSE) and the hippocampal volumetry. Civet differed significantly from Freesurfer in large frontal, parietal, temporal and occipital regions (p<0.05). In a discriminant analysis with cortical ROIs having effect size larger than 0.8, both pipelines gave no significant differences in area under the curve (AUC). Longitudinally, effect sizes were not significantly different in any of the 28 ROIs tested. Both pipelines weakly correlated with MMSE decay, showing no significant differences. Freesurfer mildly correlated with hippocampal thinning rate and differed in the supramarginal gyrus, temporal gyrus, and in the lateral occipital cortex compared to Civet (p<0.05). In a discriminant analysis with ROIs having effect size larger than 0.6, both pipelines yielded no significant differences in the AUC.
Conclusions
Civet appears slightly more sensitive to the typical AD atrophic pattern at the MCI stage, but both pipelines can accurately characterize the topography of cortical thinning at the dementia stage.
DOI•
University of Toulouse1, Washington University in St. Louis2, Sahlgrenska University Hospital3, University of Geneva4, Harvard University5, Food and Drug Administration6, University of Alabama at Birmingham7, Brigham and Women's Hospital8, Eli Lilly and Company9, Brown University10, Baylor College of Medicine11, University of California, San Diego12
TL;DR: The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials.
Abstract: For Alzheimer's disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials.
TL;DR: It is proposed that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty" and be used in clinical trials to form homogeneous groups of AD patients diagnosed by current guidelines.
Abstract: Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.
University of Antwerp1, Katholieke Universiteit Leuven2, Karolinska Institutet3, Karolinska University Hospital4, Carlos III Health Institute5, University of Navarra6, Technische Universität München7, University of Florence8, University of Barcelona9, University of Coimbra10, Autonomous University of Barcelona11, University of Lisbon12, University of Brescia13, Charles University in Prague14, University of Geneva15, University of Verona16
TL;DR: Data indicate that SQSTM1 does not play a major role in the etiology of EOAD, and burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts.
University of Geneva1, University of Barcelona2, University of Duisburg-Essen3, University of Göttingen4, University of Genoa5, Aix-Marseille University6, French Institute of Health and Medical Research7, University of Toulouse8, University of Naples Federico II9, University of Perugia10, Aristotle University of Thessaloniki11, Interbalkan Medical Center12, The Catholic University of America13, Leipzig University14, VU University Medical Center15, Maastricht University16, University of Trento17
TL;DR: It is found that within‐session averaging of two T1 images significantly improved the reproducibility of all hippocampal subfields but not that of the whole hippocampus, suggesting that the larger hippocampus subfields volume may be reliable longitudinal markers in multisite studies.
Abstract: Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of all hippocampal subfields but not that of the whole hippocampus. Volumetric and spatial reproducibility across MRI sites were very good for the whole hippocampus, CA2-3, CA4-dentate gyrus (DG), subiculum (reproducibility error∼2% and DICE > 0.90), good for CA1 and presubiculum (reproducibility error ∼ 5% and DICE ∼ 0.90), and poorer for fimbria and hippocampal fissure (reproducibility error ∼ 15% and DICE < 0.80). Spearman's correlations confirmed that test-retest reproducibility improved with volume size. Despite considerable differences of MRI scanner configurations, we found consistent hippocampal subfields volumes estimation. CA2-3, CA4-DG, and sub-CA1 (subiculum, presubiculum, and CA1 pooled together) gave test-retest reproducibility similar to the whole hippocampus. Our findings suggest that the larger hippocampal subfields volume may be reliable longitudinal markers in multisite studies.
University of Göttingen1, Sahlgrenska University Hospital2, Hospital de Sant Pau3, Statens Serum Institut4, University of Coimbra5, University of Perugia6, Università degli Studi eCampus7, Ljubljana University Medical Centre8, University of Antwerp9, Dokuz Eylül University10, Akershus University Hospital11, University of Geneva12, Universidad Miguel Hernández de Elche13, Aristotle University of Thessaloniki14, Odense University Hospital15, Instituto de Medicina Molecular16, Slovak Academy of Sciences17, Radboud University Nijmegen18, Instituto Gulbenkian de Ciência19, UCL Institute of Neurology20
TL;DR: This study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by the study design, high variation in absolute values of CSF aSyn was identified even when the same samples and same lots of assays were applied.
University of Eastern Finland1, VTT Technical Research Centre of Finland2, Imperial College London3, VU University Amsterdam4, Aristotle University of Thessaloniki5, University of Genoa6, Karolinska Institutet7, Lund University8, Heidelberg University9, University of Paris10, Maastricht University11
TL;DR: The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers.
Abstract: We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DESCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out crossvalidation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, theywere 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.
TL;DR: This noninvasive magnetic resonance imaging analysis, revealed common biomarkers between humans and mice, and could be promoted as a fully translational tool to be adopted in the preclinical investigation of therapeutic approaches.
TL;DR: In this article, a group of Borderline personality disorder (BPD) patients compared to healthy controls (HC) showed widespread lower cortical GMD compared to HC with peaks of lower density located in the dorsal frontal cortex, in the orbitofrontal cortex, the anterior and posterior cingulate, the right parietal lobe, the temporal lobe (medial temporal cortex and fusiform gyrus) and in the visual cortex.