Neuroimaging in Neurodegenerative Dementias

Abstract

Neurodegenerative dementias are characterized by insidious onset and gradual progression of cognitive dysfunction, initially relatively focal with respect to cognitive domains and brain regions involved. Neuroimaging techniques have contributed enormously to both our understanding of large-scale network specificity in neurodegenerative syndromes and our ability to make clinical diagnoses of syndromes such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), posterior cortical atrophy (PCA), logopenic primary progressive aphasia (PPA), agrammatic PPA, semantic dementia (SD), behavioral variant frontotemporal dementia (bvFTD), corticobasal syndrome (CBS), and progressive supranuclear palsy syndrome (PSPS). More importantly, rapid advances in imaging and computational techniques promise to improve our ability to make pathologic diagnoses of AD, DLB, and frontotemporal lobar degeneration (FTLD) pathologies in vivo at an early stage of illness. Neuroimaging is thus integral to the development and application of disease modifying therapies for neurodegenerative illnesses.

Keywords

neurodegeneration - neuroimaging - dementia - magnetic resonance imaging (MRI) - functional magnetic resonance imaging (fMRI) - functional connectivity magnetic resonance imaging (fcMRI) - diffusion tensor imaging (DTI) - [¹⁸F] fluorodeoxyglucose positron emission tomography (FDG-PET) - amyloid positron emission tomography - dopamine transporter (DAT) imaging - Alzheimer's disease - dementia with Lewy bodies - frontotemporal dementia

• References

• 1 Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1987
• 2 Pievani M, de Haan W, Wu T, Seeley WW, Frisoni GB. Functional network disruption in the degenerative dementias. Lancet Neurol 2011; 10 (9) 829-843
• 3 Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 2007; 8 (9) 700-711
• 4 Smith SM, Fox PT, Miller KL , et al. Correspondence of the brain's functional architecture during activation and rest. Proc Natl Acad Sci U S A 2009; 106 (31) 13040-13045
• 5 Buckner RL, Snyder AZ, Shannon BJ , et al. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005; 25 (34) 7709-7717
• 6 Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009; 62 (1) 42-52
• 7 Raj A, Kuceyeski A, Weiner M. A network diffusion model of disease progression in dementia. Neuron 2012; 73 (6) 1204-1215
• 8 Warren JD, Rohrer JD, Hardy J. Disintegrating brain networks: from syndromes to molecular nexopathies. Neuron 2012; 73 (6) 1060-1062
• 9 Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 2012; 73 (6) 1216-1227
• 10 Petersen RC. Clinical practice. Mild cognitive impairment. N Engl J Med 2011; 364 (23) 2227-2234
• 11 Morris JC. Early-stage and preclinical Alzheimer disease. Alzheimer Dis Assoc Disord 2005; 19 (3) 163-165
• 12 Sperling RA, Jack Jr CR, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med 2011; 3 (111) 111cm133
• 13 Jack Jr CR, Knopman DS, Jagust WJ , et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010; 9 (1) 119-128
• 14 Sperling RA, Aisen PS, Beckett LA , 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. Alzheimers Dement 2011; 7 (3) 280-292
• 15 Garre-Olmo J, Genís Batlle D, del Mar Fernández M , et al; Registry of Dementia of Girona Study Group (ReDeGi Study Group). Incidence and subtypes of early-onset dementia in a geographically defined general population. Neurology 2010; 75 (14) 1249-1255
• 16 Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011; 7 (3) 137-152
• 17 Hyman BT, Phelps CH, Beach TG , et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012; 8 (1) 1-13
• 18 Goldman JS, Hahn SE, Catania JW , et al; American College of Medical Genetics and the National Society of Genetic Counselors. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 2011; 13 (6) 597-605
• 19 Bird TD. Genetic aspects of Alzheimer disease. Genet Med 2008; 10 (4) 231-239
• 20 Balasa M, Gelpi E, Antonell A , et al; Neurological Tissue Bank/University of Barcelona/Hospital Clínic NTB/UB/HC Collaborative Group. Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease. Neurology 2011; 76 (20) 1720-1725
• 21 Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimers Dis 2010; 19 (4) 1401-1408
• 22 Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 2011; 10 (9) 785-796
• 23 Jack Jr CR. Alliance for aging research AD biomarkers work group: structural MRI. Neurobiol Aging 2011; 32 (Suppl. 01) S48-S57
• 24 Dubois B, Feldman HH, Jacova C , et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6 (8) 734-746
• 25 Scheltens P, Leys D, Barkhof F , et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992; 55 (10) 967-972
• 26 Albert MS, DeKosky ST, Dickson D , et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7 (3) 270-279
• 27 McKhann GM, Knopman DS, Chertkow H , 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. Alzheimers Dement 2011; 7 (3) 263-269
• 28 Fischl B, van der Kouwe A, Destrieux C , et al. Automatically parcellating the human cerebral cortex. Cereb Cortex 2004; 14 (1) 11-22
• 29 Fox NC, Freeborough PA, Rossor MN. Visualisation and quantification of rates of atrophy in Alzheimer's disease. Lancet 1996; 348 (9020) 94-97
• 30 Freeborough PA, Fox NC. The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI. IEEE Trans Med Imaging 1997; 16 (5) 623-629
• 31 Davatzikos C, Xu F, An Y, Fan Y, Resnick SM. Longitudinal progression of Alzheimer's-like patterns of atrophy in normal older adults: the SPARE-AD index. Brain 2009; 132 (Pt 8) 2026-2035
• 32 Klöppel S, Stonnington CM, Chu C , et al. Automatic classification of MR scans in Alzheimer's disease. Brain 2008; 131 (Pt 3) 681-689
• 33 Casanova R, Whitlow CT, Wagner B , et al. High dimensional classification of structural MRI Alzheimer's disease data based on large scale regularization. Front Neuroinform 2011; 5: 22
• 34 Vemuri P, Gunter JL, Senjem ML , et al. Alzheimer's disease diagnosis in individual subjects using structural MR images: validation studies. Neuroimage 2008; 39 (3) 1186-1197
• 35 Apostolova LG, Dutton RA, Dinov ID , et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol 2006; 63 (5) 693-699
• 36 Jack Jr CR, Petersen RC, Xu YC , et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999; 52 (7) 1397-1403
• 37 Morra JH, Tu Z, Apostolova LG , et al; Alzheimer's Disease Neuroimaging Initiative. Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls. Neuroimage 2009; 45 (1, Suppl) S3-S15
• 38 Apostolova LG, Mosconi L, Thompson PM , et al. Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal. Neurobiol Aging 2010; 31 (7) 1077-1088
• 39 Thompson PM, Apostolova LG. Computational anatomical methods as applied to ageing and dementia. Br J Radiol 2007; 80 (Spec No 2) S78-S91
• 40 Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage 2000; 11 (6 Pt 1) 805-821
• 41 Karas GB, Scheltens P, Rombouts SA , et al. Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease. Neuroimage 2004; 23 (2) 708-716
• 42 Whitwell JL, Shiung MM, Przybelski SA , et al. MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology 2008; 70 (7) 512-520
• 43 Chételat G, Landeau B, Eustache F , et al. Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage 2005; 27 (4) 934-946
• 44 Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 2000; 97 (20) 11050-11055
• 45 Rosas HD, Liu AK, Hersch S , et al. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology 2002; 58 (5) 695-701
• 46 Apostolova LG, Steiner CA, Akopyan GG , et al. Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease. Arch Neurol 2007; 64 (10) 1489-1495
• 47 Dickerson BC, Bakkour A, Salat DH , 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. Cereb Cortex 2009; 19 (3) 497-510
• 48 Lerch JP, Pruessner JC, Zijdenbos A, Hampel H, Teipel SJ, Evans AC. Focal decline of cortical thickness in Alzheimer's disease identified by computational neuroanatomy. Cereb Cortex 2005; 15 (7) 995-1001
• 49 Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology 2009; 72 (12) 1048-1055
• 50 Dickerson BC, Stoub TR, Shah RC , et al. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 2011; 76 (16) 1395-1402
• 51 Jack Jr CR, Dickson DW, Parisi JE , et al. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 2002; 58 (5) 750-757
• 52 Whitwell JL, Josephs KA, Murray ME , et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology 2008; 71 (10) 743-749
• 53 Vemuri P, Whitwell JL, Kantarci K , et al. Antemortem MRI based STructural Abnormality iNDex (STAND)-scores correlate with postmortem Braak neurofibrillary tangle stage. Neuroimage 2008; 42 (2) 559-567
• 54 Silverman DH. Brain 18F-FDG PET in the diagnosis of neurodegenerative dementias: comparison with perfusion SPECT and with clinical evaluations lacking nuclear imaging. J Nucl Med 2004; 45 (4) 594-607
• 55 Matsuda H. Role of neuroimaging in Alzheimer's disease, with emphasis on brain perfusion SPECT. J Nucl Med 2007; 48 (8) 1289-1300
• 56 Jagust W, Reed B, Mungas D, Ellis W, Decarli C. What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia?. Neurology 2007; 69 (9) 871-877
• 57 Silverman DH, Small GW, Chang CY , et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001; 286 (17) 2120-2127
• 58 Reiman EM. Alzheimer's Disease Biomarkers Working Group for the Alliance for Aging Research. Fluorodeoxyglucose positron emission tomography: emerging roles in the evaluation of putative Alzheimer's disease-modifying treatments. Neurobiol Aging 2011; 32 (Suppl. 01) S44-S47
• 59 Ikonomovic MD, Klunk WE, Abrahamson EE , et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 2008; 131 (Pt 6) 1630-1645
• 60 Mirra SS, Heyman A, McKeel D , et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991; 41 (4) 479-486
• 61 Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging 1997; 18 (4, Suppl) S1-S2
• 62 Klunk WE. Amyloid imaging as a biomarker for cerebral β-amyloidosis and risk prediction for Alzheimer dementia. Neurobiol Aging 2011; 32 (Suppl. 01) S20-S36
• 63 Clark CM, Schneider JA, Bedell BJ , et al; AV45-A07 Study Group. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305 (3) 275-283
• 64 Yang L, Rieves D, Ganley C. Brain amyloid imaging—FDA approval of florbetapir F18 injection. N Engl J Med 2012; 367 (10) 885-887
• 65 Bateman RJ, Xiong C, Benzinger TL , et al; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367 (9) 795-804
• 66 Schwindt GC, Black SE. Functional imaging studies of episodic memory in Alzheimer's disease: a quantitative meta-analysis. Neuroimage 2009; 45 (1) 181-190
• 67 Sperling RA, Dickerson BC, Pihlajamaki M , et al. Functional alterations in memory networks in early Alzheimer's disease. Neuromolecular Med 2010; 12 (1) 27-43
• 68 Sperling R. Potential of functional MRI as a biomarker in early Alzheimer's disease. Neurobiol Aging 2011; 32 (Suppl. 01) S37-S43
• 69 Van Dijk KR, Sperling RA. Defaulting on the default network: increased risk for dementia. Neurology 2011; 76 (6) 498-500
• 70 Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 2004; 101 (13) 4637-4642
• 71 Rombouts SA, Damoiseaux JS, Goekoop R , et al. Model-free group analysis shows altered BOLD FMRI networks in dementia. Hum Brain Mapp 2009; 30 (1) 256-266
• 72 Petrella JR, Sheldon FC, Prince SE, Calhoun VD, Doraiswamy PM. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology 2011; 76 (6) 511-517
• 73 Damoiseaux JS. Resting-state fMRI as a biomarker for Alzheimer's disease?. Alzheimers Res Ther 2012; 4 (2) 8
• 74 Tang-Wai DF, Graff-Radford NR, Boeve BF , et al. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 2004; 63 (7) 1168-1174
• 75 Crutch SJ, Lehmann M, Schott JM, Rabinovici GD, Rossor MN, Fox NC. Posterior cortical atrophy. Lancet Neurol 2012; 11 (2) 170-178
• 76 Lehmann M, Crutch SJ, Ridgway GR , et al. Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease. Neurobiol Aging 2011; 32 (8) 1466-1476
• 77 Gorno-Tempini ML, Dronkers NF, Rankin KP , et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 2004; 55 (3) 335-346
• 78 Gorno-Tempini ML, Hillis AE, Weintraub S , et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76 (11) 1006-1014
• 79 Johnson JK, Head E, Kim R, Starr A, Cotman CW. Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol 1999; 56 (10) 1233-1239
• 80 Whitwell JL, Jack Jr CR, Przybelski SA , et al. Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiol Aging 2011; 32 (9) 1531-1541
• 81 Warren JD, Fletcher PD, Golden HL. The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol 2012; 8 (8) 451-464
• 82 Migliaccio R, Agosta F, Rascovsky K , et al. Clinical syndromes associated with posterior atrophy: early age at onset AD spectrum. Neurology 2009; 73 (19) 1571-1578
• 83 Vemuri P, Simon G, Kantarci K , et al. Antemortem differential diagnosis of dementia pathology using structural MRI: differential-STAND. Neuroimage 2011; 55 (2) 522-531
• 84 Rabinovici GD, Furst AJ, Alkalay A , et al. Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain 2010; 133 (Pt 2) 512-528
• 85 Rosenbloom MH, Alkalay A, Agarwal N , et al. Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. Neurology 2011; 76 (21) 1789-1796
• 86 McKeith I, Mintzer J, Aarsland D , et al; International Psychogeriatric Association Expert Meeting on DLB. Dementia with Lewy bodies. Lancet Neurol 2004; 3 (1) 19-28
• 87 McKeith IG, Dickson DW, Lowe J , et al; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65 (12) 1863-1872
• 88 Bradshaw JM, Saling M, Anderson V, Hopwood M, Brodtmann A. Higher cortical deficits influence attentional processing in dementia with Lewy bodies, relative to patients with dementia of the Alzheimer's type and controls. J Neurol Neurosurg Psychiatry 2006; 77 (10) 1129-1135
• 89 Mori E, Shimomura T, Fujimori M , et al. Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol 2000; 57 (4) 489-493
• 90 Jellinger KA. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 2008; 116 (1) 1-16
• 91 Fujimi K, Sasaki K, Noda K , et al. Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama study. Brain Pathol 2008; 18 (3) 317-325
• 92 Taylor JP, O'Brien J. Neuroimaging of dementia with Lewy bodies. Neuroimaging Clin N Am 2012; 22 (1) 67-81, viii viii.
• 93 Ballmaier M, O'Brien JT, Burton EJ , et al. Comparing gray matter loss profiles between dementia with Lewy bodies and Alzheimer's disease using cortical pattern matching: diagnosis and gender effects. Neuroimage 2004; 23 (1) 325-335
• 94 Barber R, Ballard C, McKeith IG, Gholkar A, O'Brien JT. MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 2000; 54 (6) 1304-1309
• 95 Kantarci K, Ferman TJ, Boeve BF , et al. Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies. Neurology 2012; 79 (6) 553-560
• 96 Marshall VL, Patterson J, Hadley DM, Grosset KA, Grosset DG. Two-year follow-up in 150 consecutive cases with normal dopamine transporter imaging. Nucl Med Commun 2006; 27 (12) 933-937
• 97 McKeith I, O'Brien J, Walker Z , et al; DLB Study Group. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol 2007; 6 (4) 305-313
• 98 Walker Z, Jaros E, Walker RW , et al. Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy. J Neurol Neurosurg Psychiatry 2007; 78 (11) 1176-1181
• 99 O'Brien JT, McKeith IG, Walker Z , et al; DLB Study Group. Diagnostic accuracy of 123I-FP-CIT SPECT in possible dementia with Lewy bodies. Br J Psychiatry 2009; 194 (1) 34-39
• 100 Kantarci K, Lowe VJ, Boeve BF , et al. Multimodality imaging characteristics of dementia with Lewy bodies. Neurobiol Aging 2011; (Oct) 20
• 101 Stamelou M, de Silva R, Arias-Carrión O , et al. Rational therapeutic approaches to progressive supranuclear palsy. Brain 2010; 133 (Pt 6) 1578-1590
• 102 Mackenzie IR, Munoz DG, Kusaka H , et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 2011; 121 (2) 207-218
• 103 Rabinovici GD, Miller BL. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010; 24 (5) 375-398
• 104 Rohrer JD, Guerreiro R, Vandrovcova J , et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology 2009; 73 (18) 1451-1456
• 105 Seelaar H, Kamphorst W, Rosso SM , et al. Distinct genetic forms of frontotemporal dementia. Neurology 2008; 71 (16) 1220-1226
• 106 DeJesus-Hernandez M, Mackenzie IR, Boeve BF , et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72 (2) 245-256
• 107 Renton AE, Majounie E, Waite A , et al; ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72 (2) 257-268
• 108 Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol 2011; 10 (2) 162-172
• 109 Rascovsky K, Hodges JR, Knopman D , et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134 (Pt 9) 2456-2477
• 110 Josephs KA, Hodges JR, Snowden JS , et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 2011; 122 (2) 137-153
• 111 Kipps CM, Nestor PJ, Fryer TD, Hodges JR. Behavioural variant frontotemporal dementia: not all it seems?. Neurocase 2007; 13 (4) 237-247
• 112 Rosen HJ, Gorno-Tempini ML, Goldman WP , et al. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002; 58 (2) 198-208
• 113 Kipps CM, Davies RR, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale. Dement Geriatr Cogn Disord 2007; 23 (5) 334-342
• 114 Seeley WW, Crawford R, Rascovsky K , et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol 2008; 65 (2) 249-255
• 115 Whitwell JL, Przybelski SA, Weigand SD , et al. Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study. Brain 2009; 132 (Pt 11) 2932-2946
• 116 Davatzikos C, Resnick SM, Wu X, Parmpi P, Clark CM. Individual patient diagnosis of AD and FTD via high-dimensional pattern classification of MRI. Neuroimage 2008; 41 (4) 1220-1227
• 117 Foster NL, Heidebrink JL, Clark CM , et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain 2007; 130 (Pt 10) 2616-2635
• 118 McNeill R, Sare GM, Manoharan M , et al. Accuracy of single-photon emission computed tomography in differentiating frontotemporal dementia from Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007; 78 (4) 350-355
• 119 Tartaglia MC. Frontotemporal lobar degeneration: new understanding brings new approaches. Neuroimaging Clin N Am 2012; 22 (1) 83-97, viii viii
• 120 Zhang Y, Schuff N, Du AT , et al. White matter damage in frontotemporal dementia and Alzheimer's disease measured by diffusion MRI. Brain 2009; 132 (Pt 9) 2579-2592
• 121 Tartaglia MC, Zhang Y, Racine C , et al. Executive dysfunction in frontotemporal dementia is related to abnormalities in frontal white matter tracts. J Neurol 2012; 259 (6) 1071-1080
• 122 Zhou J, Greicius MD, Gennatas ED , et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain 2010; 133 (Pt 5) 1352-1367
• 123 Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992; 115 (Pt 6) 1783-1806
• 124 Hodges JR, Patterson K. Semantic dementia: a unique clinicopathological syndrome. Lancet Neurol 2007; 6 (11) 1004-1014
• 125 Seeley WW, Bauer AM, Miller BL , et al. The natural history of temporal variant frontotemporal dementia. Neurology 2005; 64 (8) 1384-1390
• 126 Chan D, Anderson V, Pijnenburg Y , et al. The clinical profile of right temporal lobe atrophy. Brain 2009; 132 (Pt 5) 1287-1298
• 127 Gorno-Tempini ML, Murray RC, Rankin KP, Weiner MW, Miller BL. Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase 2004; 10 (6) 426-436
• 128 Gorno-Tempini ML, Rankin KP, Woolley JD, Rosen HJ, Phengrasamy L, Miller BL. Cognitive and behavioral profile in a case of right anterior temporal lobe neurodegeneration. Cortex 2004; 40 (4-5) 631-644
• 129 Grossman M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 2010; 6 (2) 88-97
• 130 Mummery CJ, Patterson K, Price CJ, Ashburner J, Frackowiak RS, Hodges JR. A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory. Ann Neurol 2000; 47 (1) 36-45
• 131 Rosen HJ, Kramer JH, Gorno-Tempini ML, Schuff N, Weiner M, Miller BL. Patterns of cerebral atrophy in primary progressive aphasia. Am J Geriatr Psychiatry 2002; 10 (1) 89-97
• 132 Rohrer JD, Warren JD, Modat M , et al. Patterns of cortical thinning in the language variants of frontotemporal lobar degeneration. Neurology 2009; 72 (18) 1562-1569
• 133 Sapolsky D, Bakkour A, Negreira A , et al. Cortical neuroanatomic correlates of symptom severity in primary progressive aphasia. Neurology 2010; 75 (4) 358-366
• 134 Josephs KA, Duffy JR, Strand EA , et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006; 129 (Pt 6) 1385-1398
• 135 Ogar J, Slama H, Dronkers N, Amici S, Gorno-Tempini ML. Apraxia of speech: an overview. Neurocase 2005; 11 (6) 427-432
• 136 Nestor PJ, Graham NL, Fryer TD, Williams GB, Patterson K, Hodges JR. Progressive non-fluent aphasia is associated with hypometabolism centred on the left anterior insula. Brain 2003; 126 (Pt 11) 2406-2418
• 137 Rebeiz JJ, Kolodny EH, Richardson Jr EP. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 1968; 18 (1) 20-33
• 138 Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10: 333-359
• 139 Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003; 54 (Suppl. 05) S15-S19
• 140 Litvan I, Agid Y, Calne D , et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47 (1) 1-9
• 141 Mathew R, Bak TH, Hodges JR. Diagnostic criteria for corticobasal syndrome: a comparative study. J Neurol Neurosurg Psychiatry 2012; 83 (4) 405-410
• 142 Litvan I, Agid Y, Jankovic J , et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 1996; 46 (4) 922-930
• 143 Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci 2011; 45 (3) 350-353
• 144 Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain 2005; 128 (Pt 9) 1996-2005
• 145 Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011; 7 (5) 263-272
• 146 Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009; 8 (3) 270-279
• 147 Boxer AL, Geschwind MD, Belfor N , et al. Patterns of brain atrophy that differentiate corticobasal degeneration syndrome from progressive supranuclear palsy. Arch Neurol 2006; 63 (1) 81-86
• 148 Josephs KA, Whitwell JL, Dickson DW , et al. Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol Aging 2008; 29 (2) 280-289
• 149 Oba H, Yagishita A, Terada H , et al. New and reliable MRI diagnosis for progressive supranuclear palsy. Neurology 2005; 64 (12) 2050-2055
• 150 Hussl A, Mahlknecht P, Scherfler C , et al. Diagnostic accuracy of the magnetic resonance parkinsonism index and the midbrain-to-pontine area ratio to differentiate progressive supranuclear palsy from Parkinson's disease and the Parkinson variant of multiple system atrophy. Mov Disord 2010; 25 (14) 2444-2449
• 151 Whitwell JL, Jack Jr CR, Boeve BF , et al. Imaging correlates of pathology in corticobasal syndrome. Neurology 2010; 75 (21) 1879-1887
• 152 Borroni B, Premi E, Agosti C , et al. CSF Alzheimer's disease-like pattern in corticobasal syndrome: evidence for a distinct disorder. J Neurol Neurosurg Psychiatry 2011; 82 (8) 834-838
• 153 Hu WT, Rippon GW, Boeve BF , et al. Alzheimer's disease and corticobasal degeneration presenting as corticobasal syndrome. Mov Disord 2009; 24 (9) 1375-1379
• 154 Whitwell JL, Josephs KA. Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology. Nat Rev Neurol 2011; 8 (3) 131-142
• 155 Rohrer JD, Lashley T, Schott JM , et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain 2011; 134 (Pt 9) 2565-2581
• 156 Whitwell JL, Jack Jr CR, Parisi JE , et al. Imaging signatures of molecular pathology in behavioral variant frontotemporal dementia. J Mol Neurosci 2011; 45 (3) 372-378
• 157 Whitwell JL, Jack Jr CR, Parisi JE , et al. Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?. Neurology 2010; 75 (24) 2212-2220
• 158 Urwin H, Josephs KA, Rohrer JD , et al; FReJA Consortium. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 2010; 120 (1) 33-41
• 159 McMillan CT, Brun C, Siddiqui S , et al. White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration. Neurology 2012; 78 (22) 1761-1768
• 160 McMillan C, Irwin D, Powers J , et al. White matter helps in vivo dissociation between tau from TDP-43 in frontotemporal degeneration. Paper presented at: The 8th International Conference on Frontotemporal Dementias; September 5–7, 2012; Manchester, England
• 161 Borroni B, Alberici A, Premi E , et al. Brain magnetic resonance imaging structural changes in a pedigree of asymptomatic progranulin mutation carriers. Rejuvenation Res 2008; 11 (3) 585-595
• 162 Borroni B, Alberici A, Cercignani M , et al. Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD. Neurobiol Aging 2012; 33 (10) 2506-2520
• 163 Whitwell JL, Josephs KA, Avula R , et al. Altered functional connectivity in asymptomatic MAPT subjects: a comparison to bvFTD. Neurology 2011; 77 (9) 866-874
• 164 Mueller SG, Weiner MW, Thal LJ , et al. Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's Disease Neuroimaging Initiative (ADNI). Alzheimers Dement 2005; 1 (1) 55-66
• 165 Bateman RJ, Aisen PS, De Strooper B , et al. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther 2011; 3 (1) 1