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A clinicopathological approach to the diagnosis of dementia

This article has been updated

Key Points

  • Definite classification of dementia is based on the underlying neuropathology

  • Accumulation of abnormally folded proteins lies at the heart of dementia neuropathology

  • Alzheimer disease pathology can give rise to subtypes with focal onset in functional networks outside the memory system, such as language, visuospatial and behavioural executive domains

  • Frontotemporal lobar degeneration, associated with aggregates of tau, TDP-43 or FUS, can give rise to three core frontotemporal dementia syndromes and three associated syndromes

  • Clinical classification of dementia syndromes is based on diagnostic criteria that rely heavily on the specificity of affected domains and the evolution of deficits in these domains

  • In vivo biomarkers of disease include imaging findings of morphological, molecular and functional changes, both upstream and downstream of the disease processes

Abstract

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes — Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases — with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.

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Figure 1: Clinicopathological spectrum of neurodegenerative proteinopathies.
Figure 2: Patterns of brain atrophy in Alzheimer disease.
Figure 3: Possible clinicopathological correlations for frontotemporal dementia syndromes.
Figure 4: Patterns of brain atrophy in frontotemporal dementia syndromes.

Change history

  • 28 July 2017

    In the online biography for Fanny M. Elahi, 'American Academy of Neurology' was incorrectly written as 'American Association of Neurology'. This error has been corrected in the HTML version of the article.

References

  1. 1

    Brun, A., Liu, X. & Erikson, C. Synapse loss and gliosis in the molecular layer of the cerebral cortex in Alzheimer's disease and in frontal lobe degeneration. Neurodegeneration 4, 171–177 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Miller, B. L. et al. Neuroanatomy of the self: evidence from patients with frontotemporal dementia. Neurology 57, 817–821 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Alzheimer's Disease International. World Alzheimer Report 2015: the Global Impact of Dementia. Alzheimer's Disease International https://www.alz.co.uk/research/world-report-2015 (2015).

  4. 4

    Sloane, P. D. et al. The public health impact of Alzheimer's disease, 2000–2050: potential implication of treatment advances. Annu. Rev. Public Health 23, 213–231 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Katzman, R. Alzheimer's disease. N. Engl. J. Med. 314, 964–973 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    McKhann, G. M. 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. 7, 263–269 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L. & Greicius, M. D. Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    McKinley, M. P., Masiarz, F. R. & Prusiner, S. B. Reversible chemical modification of the scrapie agent. Science 214, 1259–1261 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Seeley, W. W. Selective functional, regional, and neuronal vulnerability in frontotemporal dementia. Curr. Opin. Neurol. 21, 701–707 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Jellinger, K. A. & Attems, J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol. 115, 427–436 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Matthews, F. E. et al. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med. 6, e1000180 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Lobo, A. et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54, S4–S9 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Qiu, C., Kivipelto, M. & von Strauss, E. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin. Neurosci. 11, 111–128 (2009).

    PubMed  PubMed Central  Google Scholar 

  19. 19

    Panegyres, P. K. & Frencham, K. Course and causes of suspected dementia in young adults: a longitudinal study. Am. J. Alzheimers Dis. Other Demen. 22, 48–56 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, J. R. The prevalence of frontotemporal dementia. Neurology 58, 1615–1621 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Harvey, R. J., Skelton-Robinson, M. & Rossor, M. N. The prevalence and causes of dementia in people under the age of 65 years. J. Neurol. Neurosurg. Psychiatry 74, 1206–1209 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Kelley, B. J., Boeve, B. F. & Josephs, K. A. Young-onset dementia: demographic and etiologic characteristics of 235 patients. Arch. Neurol. 65, 1502–1508 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Mercy, L., Hodges, J. R., Dawson, K., Barker, R. A. & Brayne, C. Incidence of early-onset dementias in Cambridgeshire, United Kingdom. Neurology 71, 1496–1499 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Schneider, J. A., Arvanitakis, Z., Bang, W. & Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197–2204 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Nelson, P. T. et al. Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol. 20, 66–79 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ruitenberg, A., Ott, A., van Swieten, J. C., Hofman, A. & Breteler, M. M. Incidence of dementia: does gender make a difference? Neurobiol. Aging 22, 575–580 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H. & Del Tredici, K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Braak, H. & Braak, E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–278 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Thal, D. R. et al. Sequence of Abeta-protein deposition in the human medial temporal lobe. J. Neuropathol. Exp. Neurol. 59, 733–748 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Grudzien, A. et al. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease. Neurobiol. Aging 28, 327–335 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Theofilas, P., Dunlop, S., Heinsen, H. & Grinberg, L. T. Turning on the light within: subcortical nuclei of the isodentritic core and their role in Alzheimer's disease pathogenesis. J. Alzheimers Dis. 46, 17–34 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Simic, G. et al. Monoaminergic neuropathology in Alzheimer's disease. Prog. Neurobiol. 151, 101–138 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307, 262–265 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Watts, J. C. et al. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 111, 10323–10328 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Cohen, M. L. et al. Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β. Brain 138, 1009–1022 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Qiang, W., Yau, W. M., Lu, J. X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes. Nature 541, 217–221 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Petersen, R. C. et al. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56, 303–308 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Albert, M. S. 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. 7, 270–279 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Bertram, L. & Tanzi, R. E. The genetics of Alzheimer's disease. Prog. Mol. Biol. Transl Sci. 107, 79–100 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Bertram, L., Lill, C. M. & Tanzi, R. E. The genetics of Alzheimer disease: back to the future. Neuron 68, 270–281 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349–1356 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Chouraki, V. & Seshadri, S. Genetics of Alzheimer's disease. Adv. Genet. 87, 245–294 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Desikan, R. S. et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 14, e1002258 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Baumgart, M. et al. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 11, 718–726 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Osorio, R. S. et al. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 84, 1964–1971 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Iturria-Medina, Y. et al. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Haight, T. J. et al. Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism. JAMA Neurol. 70, 1039–1045 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Janelidze, S. et al. CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol. 3, 154–165 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Ewers, M. et al. CSF biomarkers for the differential diagnosis of Alzheimer's disease: a large-scale international multicenter study. Alzheimers Dement. 11, 1306–1315 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Jack, C. R. Jr & Holtzman, D. M. Biomarker modeling of Alzheimer's disease. Neuron 80, 1347–1358 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Tosun, D. et al. Association between tau deposition and antecedent amyloid-beta accumulation rates in normal and early symptomatic individuals. Brain 140, 1499–1512 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Scholl, M. et al. PET imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Schwarz, A. J. et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139, 1539–1550 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Cho, H. et al. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann. Neurol. 80, 247–258 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Wang, Y. et al. Development of a PET/SPECT agent for amyloid imaging in Alzheimer's disease. J. Mol. Neurosci. 24, 55–62 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Garibotto, V. et al. Clinical validity of brain fluorodeoxyglucose positron emission tomography as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework. Neurobiol. Aging 52, 183–195 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Ten Kate, M. et al. Clinical validity of medial temporal atrophy as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework. Neurobiol. Aging 52, 167–182.e1 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Chetelat, G. et al. Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease. Brain 139, 2528–2539 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Reitz, C., Brayne, C. & Mayeux, R. Epidemiology of Alzheimer disease. Nat. Rev. Neurol. 7, 137–152 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Tang, M. et al. Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 15, 1317–1325 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Joshi, A., Ringman, J. M., Lee, A. S., Juarez, K. O. & Mendez, M. F. Comparison of clinical characteristics between familial and non-familial early onset Alzheimer's disease. J. Neurol. 259, 2182–2188 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Mendez, M. F., Lee, A. S., Joshi, A. & Shapira, J. S. Nonamnestic presentations of early-onset Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen. 27, 413–420 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Mesulam, M. Primary progressive aphasia pathology. Ann. Neurol. 63, 124–125 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Mesulam, M. et al. Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia. Ann. Neurol. 63, 709–719 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Spinelli, E. G. et al. Typical and atypical pathology in primary progressive aphasia variants. Ann. Neurol. 81, 430–443 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Benson, D. F., Davis, R. J. & Snyder, B. D. Posterior cortical atrophy. Arch. Neurol. 45, 789–793 (1988).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Crutch, S. J. et al. Shining a light on posterior cortical atrophy. Alzheimers Dement. 9, 463–465 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Whitwell, J. L. et al. Imaging correlates of posterior cortical atrophy. Neurobiol. Aging 28, 1051–1061 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Ossenkoppele, R. et al. The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain 138, 2732–2749 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Binetti, G. et al. Disorders of visual and spatial perception in the early stage of Alzheimer's disease. Ann. NY Acad. Sci. 777, 221–225 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Back-Madruga, C. et al. Functional ability in executive variant Alzheimer's disease and typical Alzheimer's disease. Clin. Neuropsychol. 16, 331–340 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Snowden, J. S. et al. Cognitive phenotypes in Alzheimer's disease and genetic risk. Cortex 43, 835–845 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Dickerson, B. C., Wolk, D. A. & Alzheimer's Disease Neuroimaging Initiative. Dysexecutive versus amnesic phenotypes of very mild Alzheimer's disease are associated with distinct clinical, genetic and cortical thinning characteristics. J. Neurol. Neurosurg. Psychiatry 82, 45–51 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Mez, J. et al. Faster cognitive and functional decline in dysexecutive versus amnestic Alzheimer's subgroups: a longitudinal analysis of the National Alzheimer's Coordinating Center (NACC) database. PLoS ONE 8, e65246 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Varma, A. R. et al. Evaluation of the NINCDS–ADRDA criteria in the differentiation of Alzheimer's disease and frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 66, 184–188 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Rabinovici, G. D. et al. Amyloid versus FDG–PET in the differential diagnosis of AD and FTLD. Neurology 77, 2034–2042 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Ossenkoppele, R. et al. Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement. 9, 414–421 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Grinberg, L. T. & Thal, D. R. Vascular pathology in the aged human brain. Acta Neuropathol. 119, 277–290 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Jellinger, K. A. The pathology of “vascular dementia”: a critical update. J. Alzheimers Dis. 14, 107–123 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Jellinger, K. A. Pathology and pathogenesis of vascular cognitive impairment — a critical update. Front. Aging Neurosci. 5, 17 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Gorelick, P. B. et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 2672–2713 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Kalaria, R. N. et al. Towards defining the neuropathological substrates of vascular dementia. J. Neurol. Sci. 226, 75–80 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wardlaw, J. M. Blood–brain barrier and cerebral small vessel disease. J. Neurol. Sci. 299, 66–71 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Wardlaw, J. M. et al. Blood–brain barrier permeability and long-term clinical and imaging outcomes in cerebral small vessel disease. Stroke 44, 525–527 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Kalaria, R. N. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease. Acta Neuropathol. 131, 659–685 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    McAleese, K. E. et al. Post-mortem assessment in vascular dementia: advances and aspirations. BMC Med. 14, 129 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Pendlebury, S. T. & Rothwell, P. M. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 8, 1006–1018 (2009).

    Article  Google Scholar 

  100. 100

    Zaccai, J., Ince, P. & Brayne, C. Population-based neuropathological studies of dementia: design, methods and areas of investigation — a systematic review. BMC Neurol. 6, 2 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Grinberg, L. T. et al. Prevalence of dementia subtypes in a developing country: a clinicopathological study. Clinics (Sao Paulo) 68, 1140–1145 (2013).

    Article  Google Scholar 

  102. 102

    Korczyn, A. D. The complex nosological concept of vascular dementia. J. Neurol. Sci. 203–204, 3–6 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    James, B. D., Bennett, D. A., Boyle, P. A., Leurgans, S. & Schneider, J. A. Dementia from Alzheimer disease and mixed pathologies in the oldest old. JAMA 307, 1798–1800 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Hachinski, V. Preventable senility: a call for action against the vascular dementias. Lancet 340, 645–648 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Small, G. W. Revised Ischemic Score for diagnosing multi-infarct dementia. J. Clin. Psychiatry 46, 514–517 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Roman, G. C. et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS–AIREN International Workshop. Neurology 43, 250–260 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Sachdev, P. et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis. Assoc. Disord. 28, 206–218 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Garrett, K. D. et al. The neuropsychological profile of vascular cognitive impairment — no dementia: comparisons to patients at risk for cerebrovascular disease and vascular dementia. Arch. Clin. Neuropsychol. 19, 745–757 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Rosenberg, G. A. et al. Consensus statement for diagnosis of subcortical small vessel disease. J. Cereb. Blood Flow Metab. 36, 6–25 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Wardlaw, J. M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Rosenberg, G. A., Bjerke, M. & Wallin, A. Multimodal markers of inflammation in the subcortical ischemic vascular disease type of vascular cognitive impairment. Stroke 45, 1531–1538 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Brun, A. Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch. Gerontol. Geriatr. 6, 193–208 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Baborie, A. et al. Pathological correlates of frontotemporal lobar degeneration in the elderly. Acta Neuropathol. 121, 365–371 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Mackenzie, I. R. et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 119, 1–4 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Mackenzie, I. R. et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 117, 15–18 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Neumann, M. et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–2931 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Lee, S. E. et al. Clinical characterization of bvFTD due to FUS neuropathology. Neurocase 18, 305–317 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Johnson, J. K. et al. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch. Neurol. 62, 925–930 (2005).

    PubMed  PubMed Central  Google Scholar 

  121. 121

    Yokoyama, J. S., Sirkis, D. W. & Miller, B. L. C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity. Am. J. Neurodegener. Dis. 3, 1–18 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. 122

    Goldman, J. S. et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65, 1817–1819 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Hodges, J. R. et al. Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases. Brain 133, 300–306 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Snowden, J. S. et al. Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129, 3091–3102 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Mesulam, M. et al. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch. Neurol. 64, 43–47 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Beck, J. et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 131, 706–720 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Chen-Plotkin, A. S. et al. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch. Neurol. 68, 488–497 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Snowden, J. S. et al. Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 497–505 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Watts, G. D. et al. Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Clin. Genet. 72, 420–426 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Rademakers, R. et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281–3292 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Lanata, S. C. & Miller, B. L. The behavioural variant frontotemporal dementia (bvFTD) syndrome in psychiatry. J. Neurol. Neurosurg. Psychiatry 87, 501–511 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Mioshi, E., Bristow, M., Cook, R. & Hodges, J. R. Factors underlying caregiver stress in frontotemporal dementia and Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 27, 76–81 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Wilson, R. S. et al. Life-span cognitive activity, neuropathologic burden, and cognitive aging. Neurology 81, 314–321 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Onyike, C. U. & Diehl-Schmid, J. The epidemiology of frontotemporal dementia. Int. Rev. Psychiatry 25, 130–137 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Coyle-Gilchrist, I. T. et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology 86, 1736–1743 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Seeley, W. W. et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch. Neurol. 65, 249–255 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Garcin, B. et al. Determinants of survival in behavioral variant frontotemporal dementia. Neurology 73, 1656–1661 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Diehl-Schmid, J., Perneczky, R., Koch, J., Nedopil, N. & Kurz, A. Guilty by suspicion? Criminal behavior in frontotemporal lobar degeneration. Cogn. Behav. Neurol. 26, 73–77 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Patel, A. N. & Sampson, J. B. Cognitive profile of C9orf72 in frontotemporal dementia and amyotrophic lateral sclerosis. Curr. Neurol. Neurosci. Rep. 15, 59 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Pletnikova, O. et al. Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion. Neurobiol. Aging 35, 2419.e17–2419.e21 (2014).

    CAS  Article  Google Scholar 

  145. 145

    Rankin, K. P. et al. Spontaneous social behaviors discriminate behavioral dementias from psychiatric disorders and other dementias. J. Clin. Psychiatry 69, 60–73 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Velakoulis, D., Walterfang, M., Mocellin, R., Pantelis, C. & McLean, C. Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. Br. J. Psychiatry 194, 298–305 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Kertesz, A. et al. Psychosis and hallucinations in frontotemporal dementia with the C9ORF72 mutation: a detailed clinical cohort. Cogn. Behav. Neurol. 26, 146–154 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Woolley, J. D. et al. Frontotemporal dementia and mania. Am. J. Psychiatry 164, 1811–1816 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Rosen, H. J. et al. Neuroanatomical correlates of behavioural disorders in dementia. Brain 128, 2612–2625 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Rankin, K. P. et al. Behavioral variant frontotemporal dementia with corticobasal degeneration pathology: phenotypic comparison to bvFTD with Pick's disease. J. Mol. Neurosci. 45, 594–608 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Lee, S. E. et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 137, 3047–3060 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Khan, B. K. et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J. Neurol. Neurosurg. Psychiatry 83, 358–364 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Ranasinghe, K. G. et al. Distinct subtypes of behavioral variant frontotemporal dementia based on patterns of network degeneration. JAMA Neurol. 73, 1078–1088 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Galantucci, S. et al. White matter damage in primary progressive aphasias: a diffusion tensor tractography study. Brain 134, 3011–3029 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Rogalski, E. et al. Asymmetry of cortical decline in subtypes of primary progressive aphasia. Neurology 83, 1184–1191 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Mesulam, M. M. et al. Primary progressive aphasia and the evolving neurology of the language network. Nat. Rev. Neurol. 10, 554–569 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Gorno-Tempini, M. L. et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann. Neurol. 55, 335–346 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Kramer, J. H. et al. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cogn. Behav. Neurol. 16, 211–218 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Edwards-Lee, T. et al. The temporal variant of frontotemporal dementia. Brain 120, 1027–1040 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Seeley, W. W. et al. The natural history of temporal variant frontotemporal dementia. Neurology 64, 1384–1390 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Chan, D. et al. The clinical profile of right temporal lobe atrophy. Brain 132, 1287–1298 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Geschwind, N. & Galaburda, A. M. Cerebral lateralization. Biological mechanisms, associations, and pathology: III. A hypothesis and a program for research. Arch. Neurol. 42, 634–654 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Gorno-Tempini, M. L. et al. Cognitive and behavioral profile in a case of right anterior temporal lobe neurodegeneration. Cortex 40, 631–644 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Snowden, J. S. et al. The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships. Brain 134, 2478–2492 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Mesulam, M. M., Wieneke, C., Thompson, C., Rogalski, E. & Weintraub, S. Quantitative classification of primary progressive aphasia at early and mild impairment stages. Brain 135, 1537–1553 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Mesulam, M. M. et al. Asymmetry and heterogeneity of Alzheimer's and frontotemporal pathology in primary progressive aphasia. Brain 137, 1176–1192 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Gorno-Tempini, M. L., Murray, R. C., Rankin, K. P., Weiner, M. W. & Miller, B. L. Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase 10, 426–436 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Lomen-Hoerth, C., Anderson, T. & Miller, B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59, 1077–1079 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Burrell, J. R., Kiernan, M. C., Vucic, S. & Hodges, J. R. Motor neuron dysfunction in frontotemporal dementia. Brain 134, 2582–2594 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Strong, M. J. et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 10, 131–146 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Devenney, E., Vucic, S., Hodges, J. R. & Kiernan, M. C. Motor neuron disease–frontotemporal dementia: aclinical continuum. Expert Rev. Neurother. 15, 509–522 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Höglinger, G. U. et al. Clinical diagnosis of progressive supranuclear palsy: the Movement Disorder Society criteria. Mov. Disord. 32, 853–864 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Williams, D. R. et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 130, 1566–1576 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Williams, D. R. et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128, 1247–1258 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Boxer, A. L. et al. Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease. Arch. Neurol. 69, 509–517 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  176. 176

    Massey, L. A. et al. The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy. Neurology 80, 1856–1861 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Lee, S. E. et al. Clinicopathological correlations in corticobasal degeneration. Ann. Neurol. 70, 327–340 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Armstrong, M. J. et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 80, 496–503 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Sha, S. J. et al. Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Alzheimers Res. Ther. 7, 8 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    George, S., Rey, N. L., Reichenbach, N., Steiner, J. A. & Brundin, P. α-synuclein: the long distance runner. Brain Pathol. 23, 350–357 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Mulak, A. & Bonaz, B. Brain–gut–microbiota axis in Parkinson's disease. World J. Gastroenterol. 21, 10609–10620 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Svensson, E. et al. Vagotomy and subsequent risk of Parkinson's disease. Ann. Neurol. 78, 522–529 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184

    Jellinger, K. A. & Attems, J. Prevalence and pathology of dementia with Lewy bodies in the oldest old: a comparison with other dementing disorders. Dement. Geriatr. Cogn. Disord. 31, 309–316 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185

    Walker, L. et al. Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol. 129, 729–748 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Barnes, L. L. et al. Mixed pathology is more likely in black than white decedents with Alzheimer dementia. Neurology 85, 528–534 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  187. 187

    Hall, H. et al. Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease. Brain 137, 2493–2508 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  188. 188

    Horvath, J., Herrmann, F. R., Burkhard, P. R., Bouras, C. & Kovari, E. Neuropathology of dementia in a large cohort of patients with Parkinson's disease. Parkinsonism Relat. Disord. 19, 864–868 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  189. 189

    Irwin, D. J., Lee, V. M. & Trojanowski, J. Q. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat. Rev. Neurosci. 14, 626–636 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  190. 190

    Meeus, B. et al. DLB and PDD: a role for mutations in dementia and Parkinson disease genes? Neurobiol. Aging 33, 629.e5–629.e18 (2012).

    CAS  Article  Google Scholar 

  191. 191

    Tsuang, D. et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  192. 192

    Berge, G., Sando, S. B., Rongve, A., Aarsland, D. & White, L. R. Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J. Neurol. Neurosurg. Psychiatry 85, 1227–1231 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  193. 193

    Hyun, C. H., Yoon, C. Y., Lee, H. J. & Lee, S. J. LRRK2 as a potential genetic modifier of synucleinopathies: interlacing the two major genetic factors of Parkinson's disease. Exp. Neurobiol. 22, 249–257 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  194. 194

    Bras, J. et al. Genetic analysis implicates APOE. SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum. Mol. Genet. 23, 6139–6146 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. 195

    Nalls, M. A. et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 70, 727–735 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  196. 196

    McKeith, I. Dementia with Lewy bodies and Parkinson's disease with dementia: where two worlds collide. Pract. Neurol. 7, 374–382 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  197. 197

    Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  198. 198

    Albanese, A. Diagnostic criteria for Parkinson's disease. Neurol. Sci. 24 (Suppl. 1), S23–S26 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  199. 199

    Sauerbier, A., Jenner, P., Todorova, A. & Chaudhuri, K. R. Non motor subtypes and Parkinson's disease. Parkinsonism Relat. Disord. 22 (Suppl. 1), S41–S46 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  200. 200

    Aarsland, D. et al. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology 72, 1121–1126 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  201. 201

    Gaig, C. et al. Rapidly progressive diffuse Lewy body disease. Mov. Disord. 26, 1316–1323 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  202. 202

    Schneider, J. A. et al. Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain 135, 3005–3014 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    Tiraboschi, P. et al. What best differentiates Lewy body from Alzheimer's disease in early-stage dementia? Brain 129, 729–735 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  204. 204

    Cagnin, A. et al. High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. Parkinsonism Relat. Disord. 21, 303–305 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  205. 205

    Hamilton, J. M. et al. Early visuospatial deficits predict the occurrence of visual hallucinations in autopsy-confirmed dementia with Lewy bodies. Am. J. Geriatr. Psychiatry 20, 773–781 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  206. 206

    Boot, B. P. et al. Risk factors for dementia with Lewy bodies: a case–control study. Neurology 81, 833–840 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  207. 207

    Postuma, R. B., Gagnon, J. F., Pelletier, A. & Montplaisir, J. Prodromal autonomic symptoms and signs in Parkinson's disease and dementia with Lewy bodies. Mov. Disord. 28, 597–604 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  208. 208

    Auning, E. et al. Early and presenting symptoms of dementia with lewy bodies. Dement. Geriatr. Cogn. Disord. 32, 202–208 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  209. 209

    Chiba, Y. et al. Retrospective survey of prodromal symptoms in dementia with Lewy bodies: comparison with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 33, 273–281 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  210. 210

    Ferman, T. J. et al. Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology 77, 875–882 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  211. 211

    Schenck, C. H., Boeve, B. F. & Mahowald, M. W. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 14, 744–748 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Litvan, I. et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov. Disord. 27, 349–356 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  213. 213

    Svenningsson, P., Westman, E., Ballard, C. & Aarsland, D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol. 11, 697–707 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  214. 214

    Aarsland, D., Zaccai, J. & Brayne, C. A systematic review of prevalence studies of dementia in Parkinson's disease. Mov. Disord. 20, 1255–1263 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  215. 215

    Janvin, C. C., Larsen, J. P., Aarsland, D. & Hugdahl, K. Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia. Mov. Disord. 21, 1343–1349 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  216. 216

    Emre, M. et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov. Disord. 22, 1689–1707 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  217. 217

    Olde Dubbelink, K. T. et al. Predicting dementia in Parkinson disease by combining neurophysiologic and cognitive markers. Neurology 82, 263–270 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  218. 218

    Mok, W., Chow, T. W., Zheng, L., Mack, W. J. & Miller, C. Clinicopathological concordance of dementia diagnoses by community versus tertiary care clinicians. Am. J. Alzheimers Dis. Other Demen. 19, 161–165 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  219. 219

    Toledo, J. B. et al. Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol. Commun. 1, 65 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  220. 220

    Kehagia, A. A., Barker, R. A. & Robbins, T. W. Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease. Lancet Neurol. 9, 1200–1213 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  221. 221

    Williams-Gray, C. H. et al. The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J. Neurol. Neurosurg. Psychiatry 84, 1258–1264 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  222. 222

    Teune, L. K. et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov. Disord. 25, 2395–2404 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  223. 223

    Jokinen, P. et al. [11C]PIB-, [18F]FDG–PET and MRI imaging in patients with Parkinson's disease with and without dementia. Parkinsonism Relat. Disord. 16, 666–670 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  224. 224

    Lim, S. M. et al. The 18F-FDG PET cingulate island sign and comparison to 123I-β-CIT SPECT for diagnosis of dementia with Lewy bodies. J. Nucl. Med. 50, 1638–1645 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  225. 225

    Lim, X., Yeo, J. M., Green, A. & Pal, S. The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies — a systematic review and meta-analysis. Parkinsonism Relat. Disord. 19, 851–858 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  226. 226

    Kantarci, K. et al. Antemortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy bodies. Neurobiol. Aging 33, 878–885 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  227. 227

    Brunnstrom, H., Hansson, O., Zetterberg, H., Londos, E. & Englund, E. Correlations of CSF tau and amyloid levels with Alzheimer pathology in neuropathologically verified dementia with Lewy bodies. Int. J. Geriatr. Psychiatry 28, 738–744 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  228. 228

    Thomas, A. J. et al. Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB. Neurology 88, 276–283 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  229. 229

    Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  230. 230

    Safar, J., Roller, P. P., Gajdusek, D. C. & Gibbs, C. J. Jr. Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J. Biol. Chem. 268, 20276–20284 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Puoti, G. et al. Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol. 11, 618–628 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  232. 232

    Brown, K. & Mastrianni, J. A. The prion diseases. J. Geriatr. Psychiatry Neurol. 23, 277–298 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  233. 233

    Heath, C. A. et al. Diagnosing variant Creutzfeldt–Jakob disease: a retrospective analysis of the first 150 cases in the UK. J. Neurol. Neurosurg. Psychiatry 82, 646–651 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  234. 234

    Brown, P., Brandel, J. P., Preece, M. & Sato, T. Iatrogenic Creutzfeldt–Jakob disease: the waning of an era. Neurology 67, 389–393 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  235. 235

    Will, R. G. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br. Med. Bull. 66, 255–265 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  236. 236

    Yamada, M. et al. An inherited prion disease with a PrP P105L mutation: clinicopathologic and PrP heterogeneity. Neurology 53, 181–188 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  237. 237

    Giaccone, G. et al. Neurofibrillary tangles of the Indiana kindred of Gerstmann–Straussler–Scheinker disease share antigenic determinants with those of Alzheimer disease. Brain Res. 530, 325–329 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  238. 238

    Gambetti, P., Kong, Q., Zou, W., Parchi, P. & Chen, S. G. Sporadic and familial CJD: classification and characterisation. Br. Med. Bull. 66, 213–239 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  239. 239

    Tsuji, S. & Kuroiwa, Y. Creutzfeldt–Jakob disease in Japan. Neurology 33, 1503–1506 (1983).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  240. 240

    Will, R. G. & Matthews, W. B. A retrospective study of Creutzfeldt-Jakob disease in England and Wales 1970–1979. I: clinical features. J. Neurol. Neurosurg. Psychiatry 47, 134–140 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  241. 241

    Brown, P., Cathala, F., Castaigne, P. & Gajdusek, D. C. Creutzfeldt–Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann. Neurol. 20, 597–602 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  242. 242

    Rabinovici, G. D. et al. First symptom in sporadic Creutzfeldt–Jakob disease. Neurology 66, 286–287 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  243. 243

    Krasnianski, A. et al. Clinical findings and diagnostic tests in the MV2 subtype of sporadic CJD. Brain 129, 2288–2296 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  244. 244

    Goldfarb, L. G. et al. Fatal familial insomnia and familial Creutzfeldt–Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258, 806–808 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  245. 245

    Parchi, P. et al. Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46, 224–233 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  246. 246

    Hill, A. F. et al. Investigation of variant Creutzfeldt–Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183–189 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  247. 247

    Steinhoff, B. J. et al. Diagnostic value of periodic complexes in Creutzfeldt–Jakob disease. Ann. Neurol. 56, 702–708 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  248. 248

    Forner, S. A. et al. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt–Jakob disease. Neurol. Clin. Pract. 5, 116–125 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  249. 249

    Martindale, J. et al. Sporadic Creutzfeldt–Jakob disease mimicking variant Creutzfeldt–Jakob disease. Arch. Neurol. 60, 767–770 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  250. 250

    Hamlin, C. et al. A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt–Jakob disease. Neurology 79, 547–552 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  251. 251

    Kim, M. O. & Geschwind, M. D. Clinical update of Jakob–Creutzfeldt disease. Curr. Opin. Neurol. 28, 302–310 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. 252

    Stoeck, K. et al. Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt–Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years. Brain 135, 3051–3061 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  253. 253

    Foutz, A. et al. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann. Neurol. 81, 79–92 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  254. 254

    McGuire, L. I. et al. Cerebrospinal fluid real-time quaking-induced conversion is a robust and reliable test for sporadic Creutzfeldt–Jakob disease: an international study. Ann. Neurol. 80, 160–165 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  255. 255

    Lehmann, M. et al. Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease. Proc. Natl Acad. Sci. USA 110, 11606–11611 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  256. 256

    Smith, B. N. et al. The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder. Eur. J. Hum. Genet. 21, 102–108 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  257. 257

    Snowden, J. S. et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135, 693–708 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

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Authors

Contributions

F.M.E. researched data for the article and wrote the manuscript. Both authors made substantial contributions to discussions of the content, and reviewed and edited the manuscript before submission.

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Correspondence to Fanny M. Elahi.

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The authors declare no competing financial interests.

Supplementary information

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Diagnostic criteria for selected dementia syndromes. (DOC 72 kb)

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Glossary

Acalculia

Inability to perform calculations.

Phonemic paraphasias

Errors in speech resulting in substitution of parts of the intended word by other phonemes, leading to generation of a — sometimes non-existent — word sounding similar to the target word (for example, pipe for pile, loan for moan, or papple for apple).

Visual agnosia

Inability to recognize or interpret visual stimuli despite intact vision.

Alexia

Inability to read, which comprises inability to read out loud and/or comprehend.

Ideomotor apraxia

Deficit in the ability to voluntarily plan or complete a motor task, with preservation of involuntary (automatic) motor planning when the subject is cued. This preserved ability to perform automated motoric responses to cuing contrasts with 'ideational apraxia', in which the ability to select the appropriate motor programme or sequencial steps, even in the presence of cuing, is lost.

Prosopagnosia

Inability to recognize faces, also known as 'face blindness'.

Pseudobulbar affect

Also referred to as marked emotional lability or emotional incontinence. This symptom is characterized by uncontrollable episodes of crying or laughter, proportionately in excess of the valence of an emotional stimulus.

Virchow–Robin spaces

Perivascular spaces surrounding the penetrating vessels that arise from the subarachnoid space and perforate the brain parenchyma. Prominence — in terms of visibility and numbers — of enlarged Virchow–Robin spaces has been associated with cognitive ageing, small vessel disease, and neurodegeneration.

CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited small vessel disease, with notable dysregulation of inflammatory markers and pathognomonic T2/FLAIR white matter hyperintensities in anterior temporal lobes.

Anticipation

Genetic phenomenon relating to the gradual expansion of a mutation with each generation, usually resulting in earlier age of onset and more-severe symptoms when passed on to the next generation.

Surface dyslexia and dysgraphia

Impairment in the ability to read and write words that are considered 'irregular' with regard to their spelling-to-sound correspondence (for example, friend, island or yacht), as opposed to 'regular' words (for example, fire, lemon or computer). This impairment can result in regularization errors, that is, words are erroneously spelled according to the regular phonetic rules.

Associative agnosia

Impaired recognition of visually presented objects despite intact visual perception of these objects. Also known as 'visual object agnosia'.

Hypergraphia

Compulsive and overwhelming urge to write, with potential intraindividual variability in style and content during the disease course.

Astereognosis

Inability to recognize an object by active touch alone, in the absence of primary sensory deficit.

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Elahi, F., Miller, B. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13, 457–476 (2017). https://doi.org/10.1038/nrneurol.2017.96

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