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1.  Cerebral atrophy in mild cognitive impairment and Alzheimer disease 
Neurology  2013;80(7):648-654.
Objective:
To quantify the regional and global cerebral atrophy rates and assess acceleration rates in healthy controls, subjects with mild cognitive impairment (MCI), and subjects with mild Alzheimer disease (AD).
Methods:
Using 0-, 6-, 12-, 18-, 24-, and 36-month MRI scans of controls and subjects with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we calculated volume change of whole brain, hippocampus, and ventricles between all pairs of scans using the boundary shift integral.
Results:
We found no evidence of acceleration in whole-brain atrophy rates in any group. There was evidence that hippocampal atrophy rates in MCI subjects accelerate by 0.22%/year2 on average (p = 0.037). There was evidence of acceleration in rates of ventricular enlargement in subjects with MCI (p = 0.001) and AD (p < 0.001), with rates estimated to increase by 0.27 mL/year2 (95% confidence interval 0.12, 0.43) and 0.88 mL/year2 (95% confidence interval 0.47, 1.29), respectively. A post hoc analysis suggested that the acceleration of hippocampal loss in MCI subjects was mainly driven by the MCI subjects that were observed to progress to clinical AD within 3 years of baseline, with this group showing hippocampal atrophy rate acceleration of 0.50%/year2 (p = 0.003).
Conclusions:
The small acceleration rates suggest a long period of transition to the pathologic losses seen in clinical AD. The acceleration in hippocampal atrophy rates in MCI subjects in the ADNI seems to be driven by those MCI subjects who concurrently progressed to a clinical diagnosis of AD.
doi:10.1212/WNL.0b013e318281ccd3
PMCID: PMC3590059  PMID: 23303849
2.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
3.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
4.  APOE ε4 Is Associated with Disproportionate Progressive Hippocampal Atrophy in AD 
PLoS ONE  2014;9(5):e97608.
Objectives
To investigate whether APOE ε4 carriers have higher hippocampal atrophy rates than non-carriers in Alzheimer's disease (AD), mild cognitive impairment (MCI) and controls, and if so, whether higher hippocampal atrophy rates are still observed after adjusting for concurrent whole-brain atrophy rates.
Methods
MRI scans from all available visits in ADNI (148 AD, 307 MCI, 167 controls) were used. MCI subjects were divided into “progressors” (MCI-P) if diagnosed with AD within 36 months or “stable” (MCI-S) if a diagnosis of MCI was maintained. A joint multi-level mixed-effect linear regression model was used to analyse the effect of ε4 carrier-status on hippocampal and whole-brain atrophy rates, adjusting for age, gender, MMSE and brain-to-intracranial volume ratio. The difference in hippocampal rates between ε4 carriers and non-carriers after adjustment for concurrent whole-brain atrophy rate was then calculated.
Results
Mean adjusted hippocampal atrophy rates in ε4 carriers were significantly higher in AD, MCI-P and MCI-S (p≤0.011, all tests) compared with ε4 non-carriers. After adjustment for whole-brain atrophy rate, the difference in mean adjusted hippocampal atrophy rate between ε4 carriers and non-carriers was reduced but remained statistically significant in AD and MCI-P.
Conclusions
These results suggest that the APOE ε4 allele drives atrophy to the medial-temporal lobe region in AD.
doi:10.1371/journal.pone.0097608
PMCID: PMC4039513  PMID: 24878738
5.  Standardization of Analysis Sets for Reporting Results from ADNI MRI Data 
The ADNI 3D T1-weighted MRI acquisitions provide a rich dataset for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising: screening visits, 1 year completers (subjects who all have screening, 6 and 12 month scans), two year annual completers (screening, 1, and 2 year scans), two year completers (screening, 6 months, 1 year, 18 months (MCI only) and 2 years) and complete visits (screening, 6 months, 1 year, 18 months (MCI only), 2, and 3 year (normal and MCI only) scans). As the ADNI-GO/ADNI-2 data becomes available, updated standard analysis sets will be posted regularly.
doi:10.1016/j.jalz.2012.06.004
PMCID: PMC3891834  PMID: 23110865
6.  The Importance of Group-Wise Registration in Tract Based Spatial Statistics Study of Neurodegeneration: A Simulation Study in Alzheimer's Disease 
PLoS ONE  2012;7(11):e45996.
Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer's disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a “ground truth” for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations.
doi:10.1371/journal.pone.0045996
PMCID: PMC3491011  PMID: 23139736
7.  Patterns of longitudinal brain atrophy in the logopenic variant of primary progressive aphasia 
Brain and Language  2013;127(2):121-126.
Highlights
► Patterns of cell loss in lvPPA remain asymmetrical over time. ► More anterior left hemisphere areas become involved over time. ► Right hemisphere regions become affected that mirror early left hemisphere change. ► Left hemisphere atrophy rates are greater than right hemisphere. ► Over time patients with lvPPA develop single word level processing deficits.
The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/Aβ measurements suggest Alzheimer’s disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2 years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
doi:10.1016/j.bandl.2012.12.008
PMCID: PMC3880853  PMID: 23395096
Primary progressive aphasia; Logopenic aphasia
8.  Molecular nexopathies: a new paradigm of neurodegenerative disease 
Trends in Neurosciences  2013;36(10):561-569.
Highlights
•How proteinopathies damage brain networks is a key issue in neurodegenerative disease.•Here, we outline a solution based on the concept of ‘molecular nexopathies’.•The concept is founded on specific interactions of network and protein properties.•This new paradigm has far-reaching biological and clinical implications.
Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with ‘molecular nexopathies’: specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types (e.g., clustered versus distributed connections) to particular pathogenic proteins; and differential impact of molecular effects (e.g., toxic-gain-of-function versus loss-of-function) on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology.
doi:10.1016/j.tins.2013.06.007
PMCID: PMC3794159  PMID: 23876425
neurodegeneration; dementia; neural network; nexopathy
9.  A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids☆ 
Journal of the Neurological Sciences  2013;332(1-2):141-144.
We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C > T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.
doi:10.1016/j.jns.2013.06.007
PMCID: PMC3750216  PMID: 23816250
CSF1R; HDLS; Leucoencephalopathy; Dementia; Frontal dementia; Behavioural change
10.  Posterior Cortical Atrophy 
Lancet neurology  2012;11(2):170-178.
Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management.
doi:10.1016/S1474-4422(11)70289-7
PMCID: PMC3740271  PMID: 22265212
11.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration 
Lancet Neurology  2013;12(8):822-838.
Summary
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
doi:10.1016/S1474-4422(13)70124-8
PMCID: PMC3714437  PMID: 23867200
12.  Vascular and Alzheimer's disease markers independently predict brain atrophy rate in Alzheimer's Disease Neuroimaging Initiative controls 
Neurobiology of Aging  2013;34(8):1996-2002.
This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF Aβ1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and Aβ1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and Aβ1-42 (p = 0.001) were independently associated with BSI in controls; in MCI Aβ1-42 (p < 0.001) and tau (p = 0.04) were associated with BSI. There was no evidence of independent effects of WMH or CSF measures on BSI in AD. These data support findings that vascular damage is associated with increased brain atrophy in the context of AD pathology in pre-dementia stages.
doi:10.1016/j.neurobiolaging.2013.02.003
PMCID: PMC3810644  PMID: 23522844
Alzheimer's disease; Vascular disease; Mild cognitive impairment (MCI); Volumetric MRI; Normal aging
13.  Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data 
Lancet neurology  2009;8(9):791-801.
Summary
Background
Huntington’s disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions.
Methods
This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD.
Findings
The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease.
Interpretation
We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials.
Funding
CHDI/High Q Foundation.
doi:10.1016/S1474-4422(09)70170-X
PMCID: PMC3725974  PMID: 19646924
14.  Reply: Implications of presymptomatic change in thalamus and caudate in Alzheimer’s disease 
Brain  2013;136(11):e259.
doi:10.1093/brain/awt168
PMCID: PMC3808685  PMID: 23824491
15.  White matter tract signatures of the progressive aphasias 
Neurobiology of Aging  2013;34(6):1687-1699.
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.
doi:10.1016/j.neurobiolaging.2012.12.002
PMCID: PMC3601331  PMID: 23312804
Primary progressive aphasia; DTI; Networks; White matter
16.  MIRIAD—Public release of a multiple time point Alzheimer's MR imaging dataset 
Neuroimage  2013;70(100):33-36.
The Minimal Interval Resonance Imaging in Alzheimer's Disease (MIRIAD) dataset is a series of longitudinal volumetric T1 MRI scans of 46 mild–moderate Alzheimer's subjects and 23 controls. It consists of 708 scans conducted by the same radiographer with the same scanner and sequences at intervals of 2, 6, 14, 26, 38 and 52 weeks, 18 and 24 months from baseline, with accompanying information on gender, age and Mini Mental State Examination (MMSE) scores. Details of the cohort and imaging results have been described in peer-reviewed publications, and the data are here made publicly available as a common resource for researchers to develop, validate and compare techniques, particularly for measurement of longitudinal volume change in serially acquired MR.
doi:10.1016/j.neuroimage.2012.12.044
PMCID: PMC3809512  PMID: 23274184
Alzheimer's; MRI; Longitudinal; Imaging; Database
17.  Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels 
Neuron  2013;78(1):57-64.
Summary
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
Highlights
► VCP deficiency is associated with mitochondrial depolarization ► VCP deficiency leads to increased mitochondrial respiration and uncoupling ► ATP levels are decreased in VCP-deficient cells due to lower ATP production
In this study, Bartolome et al. show that three independent pathogenic VCP mutations induce mitochondrial uncoupling, resulting in low cellular ATP production, rendering the cells more susceptible to cell death under stress-induced ischemic conditions.
doi:10.1016/j.neuron.2013.02.028
PMCID: PMC3843114  PMID: 23498975
18.  Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease 
Brain  2013;136(5):1399-1414.
Amyloid imaging studies of presymptomatic familial Alzheimer’s disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer’s disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer’s disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.
doi:10.1093/brain/awt065
PMCID: PMC3634199  PMID: 23539189
familial Alzheimer’s disease; presenilin 1 (PSEN1, PS1); presymptomatic; diffusion tensor imaging; subcortical atrophy
19.  Atrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials 
PLoS ONE  2013;8(3):e58816.
There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ∼1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ∼18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195–1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.
doi:10.1371/journal.pone.0058816
PMCID: PMC3599038  PMID: 23554933
20.  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease 
The New England journal of medicine  2012;367(9):795-804.
BACKGROUND
The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
METHODS
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
RESULTS
Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
CONCLUSIONS
We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
doi:10.1056/NEJMoa1202753
PMCID: PMC3474597  PMID: 22784036
21.  Brain MAPS: an automated, accurate and robust brain extraction technique using a template library 
NeuroImage  2010;55(3):1091-1108.
Whole brain extraction is an important pre-processing step in neuro-image analysis. Manual or semi-automated brain delineations are labour-intensive and thus not desirable in large studies, meaning that automated techniques are preferable. The accuracy and robustness of automated methods are crucial because human expertise may be required to correct any sub-optimal results, which can be very time consuming. We compared the accuracy of four automated brain extraction methods: Brain Extraction Tool (BET), Brain Surface Extractor (BSE), Hybrid Watershed Algorithm (HWA) and a Multi-Atlas Propagation and Segmentation (MAPS) technique we have previously developed for hippocampal segmentation. The four methods were applied to extract whole brains from 682 1.5T and 157 3T T1-weighted MR baseline images from the Alzheimer’s Disease Neuroimaging Initiative database. Semi-automated brain segmentations with manual editing and checking were used as the gold-standard to compare with the results. The median Jaccard index of MAPS was higher than HWA, BET and BSE in 1.5T and 3T scans (p < 0.05, all tests), and the 1st-99th centile range of the Jaccard index of MAPS was smaller than HWA, BET and BSE in 1.5T and 3T scans (p < 0.05, all tests). HWA and MAPS were found to be best at including all brain tissues (median false negative rate ≤ 0.010% for 1.5T scans and ≤ 0.019% for 3T scans, both methods). The median Jaccard index of MAPS were similar in both 1.5T and 3T scans, whereas those of BET, BSE and HWA were higher in 1.5T scans than 3T scans (p < 0.05, all tests). We found that the diagnostic group had a small effect on the median Jaccard index of all four methods. In conclusion, MAPS had relatively high accuracy and low variability compared to HWA, BET and BSE in MR scans with and without atrophy.
doi:10.1016/j.neuroimage.2010.12.067
PMCID: PMC3554789  PMID: 21195780
Automated brain extraction; skull-stripping; segmentation; MAPS; BET; BSE; HWA
22.  LoAd: A locally adaptive cortical segmentation algorithm 
NeuroImage  2011;56(3):1386-1397.
Thickness measurements of the cerebral cortex can aid diagnosis and provide valuable information about the temporal evolution of diseases such as Alzheimer's, Huntington's, and schizophrenia. Methods that measure the thickness of the cerebral cortex from in-vivo magnetic resonance (MR) images rely on an accurate segmentation of the MR data. However, segmenting the cortex in a robust and accurate way still poses a challenge due to the presence of noise, intensity non-uniformity, partial volume effects, the limited resolution of MRI and the highly convoluted shape of the cortical folds. Beginning with a well-established probabilistic segmentation model with anatomical tissue priors, we propose three post-processing refinements: a novel modification of the prior information to reduce segmentation bias; introduction of explicit partial volume classes; and a locally varying MRF-based model for enhancement of sulci and gyri. Experiments performed on a new digital phantom, on BrainWeb data and on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) show statistically significant improvements in Dice scores and PV estimation (p<10−3) and also increased thickness estimation accuracy when compared to three well established techniques.
doi:10.1016/j.neuroimage.2011.02.013
PMCID: PMC3554791  PMID: 21316470
Gaussian mixture model; Expectation-maximization; Markov Random Field; Cortical segmentation; Partial volume effect
24.  Early-onset Alzheimer disease clinical variants 
Neurology  2012;79(1):80-84.
Objective:
To assess patterns of reduced cortical thickness in different clinically defined variants of early-onset Alzheimer disease (AD) and to explore the hypothesis that these variants span a phenotypic continuum rather than represent distinct subtypes.
Methods:
The case-control study included 25 patients with posterior cortical atrophy (PCA), 15 patients with logopenic progressive aphasia (LPA), and 14 patients with early-onset typical amnestic AD (tAD), as well as 30 healthy control subjects. Cortical thickness was measured using FreeSurfer, and differences and commonalities in patterns of reduced cortical thickness were assessed between patient groups and controls. Given the difficulty of using mass-univariate statistics to test ideas of continuous variation, we use multivariate machine learning algorithms to visualize the spectrum of subjects and to assess separation of patient groups from control subjects and from each other.
Results:
Although each patient group showed disease-specific reductions in cortical thickness compared with control subjects, common areas of cortical thinning were identified, mainly involving temporoparietal regions. Multivariate analyses permitted clear separation between control subjects and patients and moderate separation between patients with PCA and LPA, while patients with tAD were distributed along a continuum between these extremes. Significant classification performance could nevertheless be obtained when every pair of patient groups was compared directly.
Conclusions:
Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation. Machine learning shows promise for syndrome separation and for identifying common anatomic patterns across syndromes that may signify a common pathology, both aspects of interest for treatment trials. Neurology® 2012;79:80–84
doi:10.1212/WNL.0b013e31825dce28
PMCID: PMC3385494  PMID: 22722624
25.  Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions 
Introduction
Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.
Methods
Following a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.
Results
Patients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.
Conclusion
Disease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.
doi:10.1186/alzrt144
PMCID: PMC3580398  PMID: 23006986

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