Brain imaging in the study of Alzheimer's disease

Over the last 20 years, there has been extraordinary progress in brain imaging research and its application to the study of Alzheimer's disease (AD). Brain imaging researchers have contributed to the scientific understanding, early detection and tracking of AD. They have set the stage for imaging techniques to play growing roles in the clinical setting, the evaluation of disease-modifying treatments, and the identification of demonstrably effective prevention therapies. They have developed ground-breaking methods, including positron emission tomography (PET) ligands to measure fibrillar amyloid-β (Aβ) deposition, new magnetic resonance imaging (MRI) pulse sequences, and powerful image analysis techniques, to help in these endeavors. Additional work is needed to develop even more powerful imaging methods, to further clarify the relationship and time course of Aβ and other disease processes in the predisposition to AD, to establish the role of brain imaging methods in the clinical setting, and to provide the scientific means and regulatory approval pathway needed to evaluate the range of promising disease-modifying and prevention therapies as quickly as possible. Twenty years from now, AD may not yet be a distant memory, but the best is yet to come.

[1]  Kewei Chen,et al.  Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. , 2011, Journal of Alzheimer's disease : JAD.

[2]  Benjamin J. Shannon,et al.  Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory , 2005, The Journal of Neuroscience.

[3]  M F Weiner,et al.  Brain blood flow in the dementias: SPECT with histopathologic correlation in 54 patients. , 1997, Radiology.

[4]  W. M. van der Flier,et al.  Detection of Alzheimer Pathology In Vivo Using Both 11C-PIB and 18F-FDDNP PET , 2009, Journal of Nuclear Medicine.

[5]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[6]  G. Alexander,et al.  Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  G. Alexander,et al.  Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism , 2005 .

[8]  C. Rowe,et al.  Relationship between atrophy and β‐amyloid deposition in Alzheimer disease , 2010, Annals of neurology.

[9]  Agneta Nordberg,et al.  Target-Specific PET Probes for Neurodegenerative Disorders Related to Dementia , 2010, The Journal of Nuclear Medicine.

[10]  Francisco Lopera,et al.  Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease , 2010, Annals of neurology.

[11]  G. Small,et al.  Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[12]  B L Holman,et al.  The scintigraphic appearance of Alzheimer's disease: a prospective study using technetium-99m-HMPAO SPECT. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[13]  G. Alexander,et al.  Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[14]  Julie C Price,et al.  Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. , 2006, Brain : a journal of neurology.

[15]  Nick C Fox,et al.  Conversion of amyloid positive and negative MCI to AD over 3 years , 2009, Neurology.

[16]  C. Rowe,et al.  Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging , 2010, Neurobiology of Aging.

[17]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[18]  Nick C Fox,et al.  Revising the definition of Alzheimer's disease: a new lexicon , 2010, The Lancet Neurology.

[19]  F Barkhof,et al.  Incidence of cerebral microbleeds , 2010, Neurology.

[20]  S Minoshima,et al.  Cerebral glucose metabolism in patients with AD and different APOE genotypes , 2005, Neurology.

[21]  G. Alexander,et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  W. Jagust,et al.  Longitudinal studies of regional cerebral metabolism in Alzheimer's disease , 1988, Neurology.

[23]  Alan Carpenter,et al.  Relationship between regional amyloid levels and cognitive performance in healthy controls, MCI subjects, and patients with alzheimer's: Phase II results from a florpiramine F18 PET imaging study , 2009, Alzheimer's & Dementia.

[24]  Jonathan K. Foster,et al.  Fluoro-2-Deoxy-D-Glucose (FDG)-PET in APOEε4 Carriers in the Australian Population , 2008 .

[25]  Satvinder S Dhaliwal,et al.  Fluoro-2-deoxy-D-glucose (FDG)-PET in APOEepsilon4 carriers in the Australian population. , 2008, Journal of Alzheimer's disease : JAD.

[26]  Gina N. LaRossa,et al.  [11C]PIB in a nondemented population , 2006, Neurology.

[27]  J. Haxby,et al.  Relations between Neuropsychological and Cerebral Metabolic Asymmetries in Early Alzheimer's Disease , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[28]  E G Tangalos,et al.  1H MR spectroscopy in common dementias , 2004, Neurology.

[29]  N. Schuff,et al.  Different regional patterns of cortical thinning in Alzheimer's disease and frontotemporal dementia. , 2006, Brain : a journal of neurology.

[30]  Martin Rossor,et al.  Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study , 2008, Neurobiology of Disease.

[31]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[32]  Brian J Bacskai,et al.  A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. , 2002, Bioorganic & medicinal chemistry letters.

[33]  Gwenn S. Smith,et al.  EARLY MARKER FOR ALZHEIMER'S DISEASE: THE ATROPHIC HIPPOCAMPUS , 1989, The Lancet.

[34]  J. Hoffman,et al.  FDG PET imaging in patients with pathologically verified dementia. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[35]  B. Miller,et al.  CME Practice parameter : Diagnosis of dementia ( an evidence-based review ) Report of the Quality Standards Subcommittee of the American Academy of Neurology , 2001 .

[36]  W. Markesbery,et al.  Hippocampal volume as an index of Alzheimer neuropathology: Findings from the Nun Study , 2002, Neurology.

[37]  Vince D. Calhoun,et al.  Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis , 2006, The Journal of Neuroscience.

[38]  S. DeKosky,et al.  Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease , 2008, Brain : a journal of neurology.

[39]  A Hofman,et al.  Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[40]  Andrei G. Vlassenko,et al.  Regional aerobic glycolysis in the human brain , 2010, Proceedings of the National Academy of Sciences.

[41]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[42]  D. Bennett,et al.  MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease☆ ☆ This research was supported by grants P01 AG09466 and P30 AG10161 from the National Institute on Aging, National Institutes of Health. , 2001, Neurobiology of Aging.

[43]  Z Walker,et al.  Microglial activation and amyloid deposition in mild cognitive impairment , 2009, Neurology.

[44]  C. Jack,et al.  11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. , 2008, Brain : a journal of neurology.

[45]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Nick C Fox,et al.  11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study , 2010, The Lancet Neurology.

[47]  Jeffrey A. James,et al.  Frequent amyloid deposition without significant cognitive impairment among the elderly. , 2008, Archives of neurology.

[48]  Roger N Gunn,et al.  In-vivo measurement of activated microglia in dementia , 2001, The Lancet.

[49]  Yaakov Stern,et al.  Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease. , 2008, Archives of neurology.

[50]  Trey Hedden Disruption of functional connectivity in clinically normal older adults harboring amyloid burden , 2010, Alzheimer's & Dementia.

[51]  Matthias J. Müller,et al.  Predicting conversion to dementia in mild cognitive impairment by volumetric and diffusivity measurements of the hippocampus , 2006, Psychiatry Research: Neuroimaging.

[52]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[53]  B. Miller,et al.  Neurodegenerative Diseases Target Large-Scale Human Brain Networks , 2009, Neuron.

[54]  Deborah Gustafson,et al.  Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. , 2004, Archives of neurology.

[55]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[56]  J. Morris,et al.  Functional deactivations: Change with age and dementia of the Alzheimer type , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[58]  Mark A Mintun,et al.  Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. , 2009, Archives of neurology.

[59]  et al.,et al.  Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET , 2002, NeuroImage.

[60]  B. L. Miller,et al.  Frontal lobe degeneration , 1991, Neurology.

[61]  C. Rowe,et al.  Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism , 2008, The Lancet Neurology.

[62]  J. Haxby,et al.  Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type. , 1990, Archives of neurology.

[63]  Laura Fratiglioni,et al.  Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. , 2002, American journal of epidemiology.

[64]  C. Jack,et al.  Ways toward an early diagnosis in Alzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) , 2005, Alzheimer's & Dementia.

[65]  G. Alexander,et al.  Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. , 2001, JAMA.

[66]  E. Salmon,et al.  18F‐flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial , 2010, Annals of neurology.

[67]  P Sachdev,et al.  Magnetic resonance spectroscopy in AD , 2001, Neurology.

[68]  Christer Halldin,et al.  Radiopharmaceuticals for positron emission tomography investigations of Alzheimer’s disease , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[69]  H. Engler,et al.  PET imaging of amyloid deposition in patients with mild cognitive impairment , 2008, Neurobiology of Aging.

[70]  Mony J. de Leon,et al.  Hypometabolism and Altered Cerebrospinal Fluid Markers in Normal Apolipoprotein E E4 Carriers with Subjective Memory Complaints , 2008, Biological Psychiatry.

[71]  J. Baron,et al.  Dissociating atrophy and hypometabolism impact on episodic memory in mild cognitive impairment. , 2003, Brain : a journal of neurology.

[72]  Simon A. Moss,et al.  b -amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease , 2007 .

[73]  Amy J. Jak,et al.  Differential Cross-Sectional and Longitudinal Impact of APOE Genotype on Hippocampal Volumes in Nondemented Older Adults , 2007, Dementia and Geriatric Cognitive Disorders.

[74]  C. DeCarli,et al.  FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. , 2007, Brain : a journal of neurology.

[75]  R. Sperling,et al.  Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline , 2010, Neurology.

[76]  C. Jack,et al.  Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI , 2005, Neurology.

[77]  Chengjie Xiong,et al.  Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease , 2011, Alzheimer's Research & Therapy.

[78]  A. Convit,et al.  Reduced hippocampal metabolism in MCI and AD , 2005, Neurology.

[79]  Cindee M. Madison,et al.  Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. , 2009, Brain : a journal of neurology.

[80]  P. Zandi,et al.  No advantage of Aβ42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies , 2008, Neurology.

[81]  L. Thurfjell,et al.  Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease , 2009, Journal of Nuclear Medicine.

[82]  Mayo Clinic,et al.  PRECLINICAL EVIDENCE OF ALZHEIMER’S DISEASE IN PERSONS HOMOZYGOUS FOR THE , 2000 .

[83]  H. Rusinek,et al.  Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer’s disease , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[84]  J. Schneider,et al.  Neuropathology of older persons without cognitive impairment from two community-based studies , 2006, Neurology.

[85]  Majaz Moonis,et al.  Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees , 2007, The Journal of Neuroscience.

[86]  Anatol C. Kreitzer,et al.  Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer's Disease , 2007, Neuron.

[87]  C. Rowe,et al.  Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease , 2011, Annals of neurology.

[88]  W. Jagust,et al.  Aβ amyloid and glucose metabolism in three variants of primary progressive aphasia , 2008, Annals of neurology.

[89]  B L Holman,et al.  Preclinical prediction of Alzheimer's disease using SPECT , 1998, Neurology.

[90]  Lars Farde,et al.  Characterization of AZD4694, a novel fluorinated Aβ plaque neuroimaging PET radioligand , 2010, Journal of neurochemistry.

[91]  et al.,et al.  Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) , 2009, NeuroImage.

[92]  M. Albert,et al.  Medial temporal lobe function and structure in mild cognitive impairment , 2004, Annals of neurology.

[93]  Cindee M. Madison,et al.  Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI , 2011, Neurobiology of Aging.

[94]  K. Herholz,et al.  Functional interactions of the entorhinal cortex: an 18F-FDG PET study on normal aging and Alzheimer's disease. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[95]  M D Devous,et al.  SPECT Study of Regional Cerebral Blood Flow in Alzheimer Disease , 1986, Journal of computer assisted tomography.

[96]  William J. Jagust,et al.  Lifespan brain activity, β-amyloid, and Alzheimer's disease , 2011, Trends in Cognitive Sciences.

[97]  M. Viitanen,et al.  PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment , 2007, Neurology.

[98]  D. Perani,et al.  MCI conversion to dementia and the APOE genotype , 2004, Neurology.

[99]  N. Foster,et al.  Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease , 1997, Annals of neurology.

[100]  Takahira Yamauchi,et al.  Abnormalities of the uncinate fasciculus and posterior cingulate fasciculus in mild cognitive impairment and early Alzheimer's disease: A diffusion tensor tractography study , 2009, Brain Research.

[101]  Richard J. Caselli,et al.  Correlations Between Apolipoprotein E ε4 Gene Dose and Whole Brain Atrophy Rates , 2007 .

[102]  Timo Grimmer,et al.  Clinical severity of Alzheimer's disease is associated with PIB uptake in PET , 2009, Neurobiology of Aging.

[103]  L. Ferrucci,et al.  Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB , 2010, Neurology.

[104]  Keith A. Johnson,et al.  Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease , 2009, The Journal of Neuroscience.

[105]  Michael E Phelps,et al.  Influence of cognitive status, age, and APOE-4 genetic risk on brain FDDNP positron-emission tomography imaging in persons without dementia. , 2009, Archives of general psychiatry.

[106]  A Hofman,et al.  Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes , 2002, Neurology.

[107]  J. Kaye,et al.  Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia , 1997, Neurology.

[108]  Keith A. Johnson,et al.  Cognition, Reserve, and Amyloid Deposition in Normal Aging , 2009, Annals of neurology.

[109]  J. Baron,et al.  FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment , 2005, Neurocase.

[110]  A. Convit,et al.  Hippocampal formation glucose metabolism and volume losses in MCI and AD , 2001, Neurobiology of Aging.

[111]  Eric Westman,et al.  Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation , 2011, Neurobiology of Aging.

[112]  J. Baron,et al.  Mild cognitive impairment , 2003, Neurology.

[113]  C. Jack,et al.  Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD , 2004, Neurology.

[114]  G. Linazasoro,et al.  IMAGING β-AMYLOID BURDEN IN AGING AND DEMENTIA , 2008, Neurology.

[115]  Jeffrey A. James,et al.  Amyloid imaging in mild cognitive impairment subtypes , 2009, Annals of neurology.

[116]  N. Foster,et al.  Alzheimer's disease , 1983, Neurology.

[117]  Hidekazu Tomimoto,et al.  SILENT ISCHEMIC INFARCTS ARE ASSOCIATED WITH HEMORRHAGE BURDEN IN CEREBRAL AMYLOID ANGIOPATHY , 2010, Neurology.

[118]  C. Jack,et al.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease , 2009, Brain : a journal of neurology.

[119]  Julie Price,et al.  Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. , 2009, Archives of neurology.

[120]  J. Baron,et al.  In Vivo Mapping of Gray Matter Loss with Voxel-Based Morphometry in Mild Alzheimer's Disease , 2001, NeuroImage.

[121]  M. D. de Leon,et al.  Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[122]  P. Scheltens,et al.  Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria , 2007, The Lancet Neurology.

[123]  D. Davies,et al.  MYOCARDIAL DISORDERS IN THE ELDERLY. , 1963, Lancet.

[124]  Rachel L. Mistur,et al.  FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[125]  John X. Morris,et al.  Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition , 2010, Proceedings of the National Academy of Sciences.

[126]  Yaakov Stern,et al.  Physical activity, diet, and risk of Alzheimer disease. , 2009, JAMA.

[127]  N. Schuff,et al.  Headache and cerebral venous air embolism , 2007, Neurology.

[128]  Anders M. Fjell,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E ɛ4 , 2008, Neurobiology of Aging.

[129]  Cindee M. Madison,et al.  Comparing predictors of conversion and decline in mild cognitive impairment , 2010, Neurology.

[130]  P. Tariot,et al.  Alzheimer's prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible. , 2010, Biomarkers in medicine.

[131]  K. Ball,et al.  Long-term effects of cognitive training on everyday functional outcomes in older adults. , 2006, JAMA.

[132]  Alistair Burns,et al.  Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205–242; (1968) 7, 331–356 , 1997 .

[133]  P. Dupont,et al.  Abeta amyloid deposition in the language system and how the brain responds. , 2007, Brain : a journal of neurology.

[134]  D. Harvey,et al.  Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD , 2006, Neurology.

[135]  Brigitte Landeau,et al.  Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: A longitudinal MRI study , 2005, NeuroImage.

[136]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup , 2011 .

[137]  J. Foster,et al.  Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. , 2008, JAMA.

[138]  S. Minoshima,et al.  In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease , 1999, Neurology.

[139]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[140]  Elena Salvatore,et al.  In Vivo Imaging of Neurotransmission and Brain Receptors in Dementia , 2008, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[141]  T. J. Grabowski,et al.  Two-year followup of amyloid deposition in patients with Alzheimer's disease , 2007 .

[142]  G. Fein,et al.  Changes of hippocampal N-acetyl aspartate and volume in Alzheimer's disease , 1997, Neurology.

[143]  F. Schmitt,et al.  Assessing Utility of Single Photon Emission Computed Tomography (SPECT) Scan in Alzheimer Disease: Correlation with Cognitive Severity , 1990, Alzheimer disease and associated disorders.

[144]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[145]  Klaus P. Ebmeier,et al.  A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease , 2011, Neurobiology of Aging.

[146]  H Lundqvist,et al.  Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment. , 1997, Dementia and geriatric cognitive disorders.

[147]  R. Coleman,et al.  Use of florbetapir-PET for imaging beta-amyloid pathology. , 2011, JAMA.

[148]  F. Fazio,et al.  Impairment of Neocortical Metabolism Predicts Progression in Alzheimer’s Disease , 1999, Dementia and Geriatric Cognitive Disorders.

[149]  Michael W. Weiner,et al.  Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: Findings from the Alzheimer's Disease Neuroimaging Initiative , 2010, NeuroImage.

[150]  G. Alexander,et al.  Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. , 2002, The American journal of psychiatry.

[151]  D. Head,et al.  Amyloid Plaques Disrupt Resting State Default Mode Network Connectivity in Cognitively Normal Elderly , 2010, Biological Psychiatry.

[152]  Lenore J Launer,et al.  Reducing the Risk of Dementia: Efficacy of Long-Term Treatment of Hypertension , 2006, Stroke.

[153]  B. Långström,et al.  The use of PET in Alzheimer disease , 2010, Nature Reviews Neurology.

[154]  D. Bennett,et al.  White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study , 2006, Neurobiology of Aging.

[155]  J C Mazziotta,et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. , 1995, JAMA.

[156]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[157]  E. Tangalos,et al.  CME Practice parameter: , 2022 .

[158]  Cynthia K Thompson,et al.  Anatomy of Language Impairments in Primary Progressive Aphasia , 2011, The Journal of Neuroscience.

[159]  Paul M. Thompson,et al.  Characterizing Alzheimer's disease using a hypometabolic convergence index , 2011, NeuroImage.

[160]  Keith A. Johnson,et al.  Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia , 2009, Neuron.

[161]  E. Sullivan,et al.  Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease , 2000, The Lancet.

[162]  Nick C. Fox,et al.  The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging and Alzheimer's Association workgroup , 2011 .

[163]  A. Drzezga,et al.  Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[164]  A. Fagan,et al.  Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. , 2009, Archives of neurology.

[165]  J. Morris,et al.  The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals , 2008, Cerebral cortex.

[166]  P. Bartenstein,et al.  Association between Cognitive Performance and Cortical Glucose Metabolism in Patients with Mild Alzheimer’s Disease , 2005, Dementia and Geriatric Cognitive Disorders.

[167]  Andrew J. Saykin,et al.  Regional brain atrophy in cognitively intact adults with a single APOE ε4 allele , 2006, Neurology.

[168]  Dong Young Lee,et al.  Topographic Patterns of Brain Functional Impairment Progression According to Clinical Severity Staging in 116 Alzheimer Disease Patients: FDG-PET Study , 2007, Alzheimer disease and associated disorders.

[169]  Eric M. Reiman,et al.  Brain Imaging in the Evaluation of Putative Alzheimer’s Disease-Slowing, Risk-Reducing and Prevention Therapies , 2009 .

[170]  Deanna Greenstein,et al.  Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study , 2007, The Lancet Neurology.

[171]  Tyler E. Benedum,et al.  Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain , 2009, Journal of Nuclear Medicine.

[172]  C. Rowe,et al.  Characterization of PiB Binding to White Matter in Alzheimer Disease and Other Dementias , 2009, Journal of Nuclear Medicine.

[173]  Masanori Nakagawa,et al.  High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types. , 2009, Archives of neurology.

[174]  Lars T Westlye,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. , 2008, Neurobiology of aging.

[175]  C. Jack,et al.  Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment , 1999, Neurology.

[176]  Richard S. J. Frackowiak,et al.  Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease , 1995, Neuroscience Letters.

[177]  Michael D. Greicius,et al.  Relationships between β-amyloid and functional connectivity in different components of the default mode network in aging. , 2011, Cerebral cortex.

[178]  Danielle J. Harvey,et al.  The Alzheimer's Disease Neuroimaging Initiative: Annual change in biomarkers and clinical outcomes , 2010, Alzheimer's & Dementia.

[179]  R. V. Van Heertum,et al.  SPECT perfusion imaging in the diagnosis of Alzheimer’s disease , 2001, Neurology.

[180]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup , 2011 .

[181]  Gina N. LaRossa,et al.  Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans , 2006, Annals of neurology.

[182]  C. Rowe,et al.  Imaging β-amyloid burden in aging and dementia , 2007, Neurology.

[183]  M. Greicius,et al.  Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI , 2004, Proc. Natl. Acad. Sci. USA.

[184]  Daniel Bandy,et al.  Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. , 2010, Archives of neurology.

[185]  Susan M Resnick,et al.  In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. , 2011, Archives of neurology.

[186]  V. Calhoun,et al.  Default mode network connectivity in stable vs progressive mild cognitive impairment , 2011, Neurology.

[187]  Nick C Fox,et al.  Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease: power calculations and estimates of sample size to detect treatment effects. , 2000, Archives of neurology.