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Cited by 378Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMemory and Neural Mechanisms

Thalamic pathology and memory loss in early Alzheimer’s disease: moving the focus from the medial temporal lobe to Papez circuit

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Aggleton, John P., Pralus, Agathe, Nelson, Andrew J. D., Hornberger, Michael·2016·Brain
DOI 10.1093/brain/aww083PMC PMC4939698
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Abstract

It is widely assumed that incipient protein pathology in the medial temporal lobe instigates the loss of episodic memory in Alzheimer's disease, one of the earliest cognitive deficits in this type of dementia. Within this region, the hippocampus is seen as the most vital for episodic memory. Consequently, research into the causes of memory loss in Alzheimer's disease continues to centre on hippocampal dysfunction and how disease-modifying therapies in this region can potentially alleviate memory symptomology. The present review questions this entrenched notion by bringing together findings from post-mortem studies, non-invasive imaging (including studies of presymptomatic, at-risk cases) and genetically modified animal models. The combined evidence indicates that the loss of episodic memory in early Alzheimer's disease reflects much wider neurodegeneration in an extended mnemonic system (Papez circuit), which critically involves the limbic thalamus. Within this system, the anterior thalamic nuclei are prominent, both for their vital contributions to episodic memory and for how these same nuclei appear vulnerable in prodromal Alzheimer's disease. As thalamic abnormalities occur in some of the earliest stages of the disease, the idea that such changes are merely secondary to medial temporal lobe dysfunctions is challenged. This alternate view is further strengthened by the interdependent relationship between the anterior thalamic nuclei and retrosplenial cortex, given how dysfunctions in the latter cortical area provide some of the earliest in vivo imaging evidence of prodromal Alzheimer's disease. Appreciating the importance of the anterior thalamic nuclei for memory and attention provides a more balanced understanding of Alzheimer's disease. Furthermore, this refocus on the limbic thalamus, as well as the rest of Papez circuit, would have significant implications for the diagnostics, modelling, and experimental treatment of cognitive symptoms in Alzheimer's disease.

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  1. Acosta-Cabronero J Nestor PJ. Diffusion tensor imaging in Alzheimer’s disease: insights into the limbic-diencephalic network and methodological considerations. Front Aging Neurosci 2014; 6: 266. doi:10.3389/fnagi.2014.00266 25324775 PMC4183111 · DOI
  2. Adamson MM Landy KM Duong S Fox-Bosetti S Ashford JW Murphy GM,. Apolipoprotein E epsilon4 influences on episodic recall and brain structures in aging pilots. Neurobiol Aging 2010; 31: 1059 – 63. doi:10.1016/j.neurobiolaging.2008.07.017 18760504 PMC2858239 · DOI
  3. Aggleton JP. Multiple anatomical systems embedded within the primate medial temporal lobe: implications for hippocampal function. Neurosci Biobehav Rev 2012; 36: 1579 – 96. doi:10.1016/j.neubiorev.2011.09.005 21964564 · DOI
  4. Aggleton JP Brown MW. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci 1999; 22: 425 – 44; discussion 444–89. doi:10.1017/S0140525X99002034 11301518 · DOI · Paper page
  5. Aggleton JP Desimone R Mishkin M. The origin, course, and termination of the hippocampothalamic projections in the macaque. J Comp Neurol 1986; 243: 409 – 21. doi:10.1002/cne.902430310 3512627 · DOI
  6. Aggleton JP Nelson AJD. Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits? Neurosci Biobehav Rev 2015; 54: 131 – 44. doi:10.1016/j.neubiorev.2014.08.013 25195980 PMC4462592 · DOI
  7. Aggleton JP Pearce JM. Neural systems underlying episodic memory: insights from animal research. Philos Trans R Soc B Biol Sci 2001; 356: 1467 – 82. doi:10.1098/rstb.2001.0946 PMC1088529 11571037 · DOI
  8. Aggleton JP Saunders RC Wright NF Vann SD. The origin of projections from the posterior cingulate and retrosplenial cortices to the anterior, medial dorsal and laterodorsal thalamic nuclei of macaque monkeys. Eur J Neurosci 2014; 39: 107 – 23. doi:10.1111/ejn.12389 24134130 PMC4112842 · DOI
  9. Aizenstein HJ Nebes RD Saxton JA Price JC Mathis CA Tsopelas ND,. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 2008; 65: 1509 – 17. doi:10.1001/archneur.65.11.1509 19001171 PMC2636844 · DOI · Paper page
  10. Albasser MM Poirier GL Warburton EC Aggleton JP. Hippocampal lesions halve immediate-early gene protein counts in retrosplenial cortex activity: distal dysfunctions in a spatial memory system. Eur J Neurosci 2007; 26: 1254 – 66. doi:10.1111/j.1460-9568.2007.05753.x 17767503 · DOI
  11. Amaral DG Cowan WM. Subcortical afferents to the hippocampal formation in the monkey. J Comp Neurol 1980; 189: 573 – 91. doi:10.1002/cne.901890402 6769979 · DOI · Paper page
  12. Amieva H Mokri H Le Goff M Meillon C Jacqmin-Gadda H Foubert-Samier A,. Compensatory mechanisms in higher-educated subjects with Alzheimer’s disease: a study of 20 years of cognitive decline. Brain 2014; 137: 1167 – 75. doi:10.1093/brain/awu035 24578544 · DOI
  13. Belleville S Chertkow H Gauthier S. Working memory and control of attention in persons with Alzheimer’s disease and mild cognitive impairment. Neuropsychology 2007; 21: 458 – 69. doi:10.1037/0894-4105.21.4.458 17605579 · DOI
  14. Braak H Braak E. Alzheimer’s disease affects limbic nuclei of the thalamus. Acta Neuropathol 1991b; 81: 261 – 8. 1711755
  15. Braak H Griffing K Braak E. Neuroanatomy of Alzheimer’s disease. Alzheimer’s Res 1997; 3: 235 – 47.
  16. Byrne P Becker S Burgess N. Remembering the past and imagining the future: a neural model of spatial memory and imagery. Psychol Rev 2007; 114: 340 – 75. doi:10.1037/0033-295X.114.2.340 17500630 PMC2678675 · DOI · Paper page
  17. Cai S Huang L Zou J Jing L Zhai B Ji G,. Changes in thalamic connectivity in the early and late stages of amnestic mild cognitive impairment: a resting-state functional magnetic resonance study from ADNI. PLoS One 2015; 10: e0115573. doi:10.1371/journal.pone.0115573 25679386 PMC4332494 · DOI
  18. Caine D Hodges JR. Heterogeneity of semantic and visuospatial deficits in early Alzheimer’s disease. Neuropsychology 2001; 15: 155 – 64. 11324859
  19. Carlesimo GA Lombardi MG Caltagirone C. Vascular thalamic amnesia: a reappraisal. Neuropsychologia 2011; 49: 777 – 89. doi:10.1016/j.neuropsychologia.2011.01.026 21255590 · DOI · Paper page
  20. Chen N. Dong S. Yan T. Yan N. Ma Y. Yu C. High-frequency stimulation of anterior nucleus thalamus improves impaired cognitive function induced by intra-hippocampal injection of Aβ1-40 in rats. Chin Med J (Engl) 2014; 127: 125 – 9. 24384437
  21. Chiang GC Zhan W Schuff N Weiner MW. White matter alterations in cognitively normal apoE ϵ2 carriers: insight into Alzheimer resistance? Am J Neuroradiol 2012; 33: 1392 – 7. doi:10.3174/ajnr.A2984 22383234 PMC3951461 · DOI · Paper page
  22. Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW,. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921 – 3. 8346443
  23. Craig LA Hong NS McDonald RJ. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci Biobehav Rev 2011; 35: 1397 – 409. doi:10.1016/j.neubiorev.2011.03.001 21392524 · DOI
  24. Cross L Brown MW Aggleton JP Warburton EC. The medial dorsal thalamic nucleus and the medial prefrontal cortex of the rat function together to support associative recognition and recency but not item recognition. Learn Mem 2012; 20: 41 – 50. doi:10.1101/lm.028266.112 23263843 PMC3533127 · DOI · Paper page
  25. Danet L Barbeau EJ Eustache P Planton M Raposo N Sibon I,. Thalamic amnesia after infarct: the role of the mammillothalamic tract and mediodorsal nucleus. Neurology 2015; 85: 2107 – 15. doi:10.1212/WNL.0000000000002226 26567269 PMC4691690 · DOI
  26. Dannhauser TM Walker Z Stevens T Lee L Seal M Shergill SS. The functional anatomy of divided attention in amnestic mild cognitive impairment. Brain 2005; 128: 1418 – 27. doi:10.1093/brain/awh413 15705612 · DOI · Paper page
  27. de Bourbon-Teles J Bentley P Koshino S Shah K Dutta A Malhotra P,. Thalamic control of human attention driven by memory and learning. Curr Biol 2014; 24: 993 – 9. doi:10.1016/j.cub.2014.03.024 24746799 PMC4012133 · DOI
  28. de Jong LW van der Hiele K Veer IM Houwing JJ Westendorp RGJ Bollen ELEM,. Strongly reduced volumes of putamen and thalamus in Alzheimer’s disease: an MRI study. Brain 2008; 131: 3277 – 85. doi:10.1093/brain/awn278 19022861 PMC2639208 · DOI · Paper page
  29. de Oliveira MS Balthazar MLF D’Abreu A Yasuda CL Damasceno BP Cendes F,. MR Imaging texture analysis of the corpus callosum and thalamus in amnestic mild cognitive impairment and mild alzheimer disease. Am J Neuroradiol 2010; 32: 60 – 6. doi:10.3174/ajnr.A2232 20966061 PMC7964940 · DOI
  30. DeVito JL. Subcortical projections to the hippocampal formation in squirrel monkey (Saimira sciureus). Brain Res Bull 1980; 5: 285 – 9. 6772284
  31. Diana RA Yonelinas AP Ranganath C. Imaging recollection and familiarity in the medial temporal lobe: a three-component model. Trends Cogn Sci 2007; 11: 379 – 86. doi:10.1016/j.tics.2007.08.001 17707683 · DOI
  32. Dias R Robbins TW Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature 1996; 380: 69 – 72. doi:10.1038/380069a0 8598908 · DOI · Paper page
  33. Dillingham CM Frizzati A Nelson AJD Vann SD. How do mammillary body inputs contribute to anterior thalamic function? Neurosci Biobehav Rev 2015; 54: 108 – 19. doi:10.1016/j.neubiorev.2014.07.025 25107491 PMC4462591 · DOI
  34. Drzezga A Becker JA Van Dijk KRA Sreenivasan A Talukdar T Sullivan C,. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 2011; 134: 1635 – 46. doi:10.1093/brain/awr066 21490054 PMC3102239 · DOI
  35. Dubois B Feldman HH Jacova C Cummings JL Dekosky ST Barberger-Gateau P,. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118 – 27. doi:10.1016/S1474-4422(10)70223-4 20934914 · DOI · Paper page
  36. Dumont JR Amin E Poirier GL Albasser MM Aggleton JP. Anterior thalamic nuclei lesions in rats disrupt markers of neural plasticity in distal limbic brain regions. Neuroscience 2012; 224: 81 – 101. doi:10.1016/j.neuroscience.2012.08.027 22917615 PMC3480641 · DOI
  37. Dumont JR Petrides M Sziklas V. Fornix and retrosplenial contribution to a hippocampo-thalamic circuit underlying conditional learning. Behav Brain Res 2010; 209: 13 – 20. doi:10.1016/j.bbr.2009.12.040 20060426 · DOI · Paper page
  38. Encinas JM Hamani C Lozano AM Enikolopov G. Neurogenic hippocampal targets of deep brain stimulation. J Comp Neurol 2011; 519: 6 – 20. doi:10.1002/cne.22503 21120924 PMC3042399 · DOI
  39. Faber C Zahneisen B Tippmann F Schroeder A Fahrenholz F. Gradient-echo and CRAZED imaging for minute detection of Alzheimer plaques in an APPV717I × ADAM10-dn mouse model. Magn Reson Med 2007; 57: 696 – 703. doi:10.1002/mrm.21201 17390347 · DOI
  40. Frisch S Dukart J Vogt B Horstmann A Becker G Villringer A,. dissociating memory networks in early alzheimer’s disease and frontotemporal lobar degeneration - a combined study of hypometabolism and atrophy. PLoS One 2013; 8: e55251. doi:10.1371/journal.pone.0055251 23457466 PMC3573064 · DOI
  41. Frisoni GB Lorenzi M Caroli A Kemppainen N Nagren K Rinne JO. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 2009; 72: 1504 – 11. doi:10.1212/WNL.0b013e3181a2e896 19398705 · DOI
  42. Garden DLF Massey PV Caruana DA Johnson B Warburton EC Aggleton JP,. Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia. Brain 2009; 132: 1847 – 57. doi:10.1093/brain/awp090 19403787 · DOI
  43. George S Rönnbäck A Gouras GK Petit GH Grueninger F Winblad B,. Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun 2014; 2: 17. doi:10.1186/2051-5960-2-17 24517102 PMC3932948 · DOI · Paper page
  44. Gurevicius K Lipponen A Tanila H. Increased cortical and thalamic excitability in freely moving appswe/ps1de9 mice modeling epileptic activity associated with alzheimer’s disease. Cereb Cortex 2013; 23: 1148 – 58. doi:10.1093/cercor/bhs105 22581851 · DOI
  45. Hamani C Stone SS Garten A Lozano AM Winocur G. Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp Neurol 2011; 232: 100 – 4. doi:10.1016/j.expneurol.2011.08.023 21906593 · DOI
  46. Hao J Li K Li K Zhang D Wang W Yang Y,. Visual attention deficits in Alzheimer’s disease: an fMRI study. Neurosci Lett 2005; 385: 18 – 23. doi:10.1016/j.neulet.2005.05.028 15970381 · DOI
  47. Harding A Halliday G Caine D Kril J. Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 2000; 123: 141 – 54. 10611128
  48. Heilman KM Bowers D Watson RT Day A Valenstein E Hammond E,. Frontal hypermetabolism and thalamic hypometabolism in a patient with abnormal orienting and retrosplenial amnesia. Neuropsychologia 1990; 28: 161 – 9. 2314571
  49. Henry J Petrides M St-Laurent M Sziklas V. Spatial conditional associative learning: effects of thalamo-hippocampal disconnection in rats. Neuroreport 2004; 15: 2427 – 31. 15640769
  50. Hooper MW Vogel FS. The limbic system in Alzheimer’s disease: a neuropathologic investigation. Am J Pathol 1976; 85: 1 – 20. 135514 PMC2032549
  51. Hornberger M Wong S Tan R Irish M Piguet O Kril J,. In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer’s disease. Brain 2012; 135: 3015 – 25 doi:10.1093/brain/aws239 23012333 · DOI
  52. Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S,. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274: 99 – 102. 8810256
  53. Irish M Devenney E Wong S Dobson-Stone C Kwok JB Piguet O,. Neural substrates of episodic memory dysfunction in behavioural variant frontotemporal dementia with and without C9ORF72 expansions. NeuroImage Clin 2013; 2: 836 – 43. doi:10.1016/j.nicl.2013.06.005 24179835 PMC3778250 · DOI
  54. Jack CR Knopman DS Jagust WJ Petersen RC Weiner MW Aisen PS,. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12: 207 – 16. doi:10.1016/S1474-4422(12)70291-0 23332364 PMC3622225 · DOI · Paper page
  55. Jankowski MM Passecker J Islam MN Vann S Erichsen JT Aggleton JP,. Evidence for spatially-responsive neurons in the rostral thalamus. Front Behav Neurosci 2015; 9: 256 doi:10.3389/fnbeh.2015.00256 26528150 PMC4602090 · DOI
  56. Jenkins TA Amin E Brown MW Aggleton JP. Changes in immediate early gene expression in the rat brain after unilateral lesions of the hippocampus. Neuroscience 2006; 137: 747 – 59 doi:10.1016/j.neuroscience.2005.09.034 16298079 · DOI
  57. Jenkins TA Dias R Amin E Brown MW Aggleton JP. Fos imaging reveals that lesions of the anterior thalamic nuclei produce widespread limbic hypoactivity in rats. J Neurosci 2002; 22: 5230 – 8. 12077218 PMC6757752
  58. Jenkins TA Vann SD Amin E Aggleton JP. Anterior thalamic lesions stop immediate early gene activation in selective laminae of the retrosplenial cortex: evidence of covert pathology in rats? Eur J Neurosci 2004; 19: 3291 – 304. doi:10.1111/j.0953-816X.2004.03421.x 15217385 · DOI
  59. Jones DT Mateen FJ Lucchinetti CF Jack CR Welker KM. Default mode network disruption secondary to a lesion in the anterior thalamus. Arch Neurol 2011; 68: 242 – 7. doi:10.1001/archneurol.2010.259 20937938 · DOI
  60. Knight WD Okello AA Ryan NS Turkheimer FE Rodriguez Martinez de Llano S Edison P,. Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers. Brain 2010; 134: 293 – 300. doi:10.1093/brain/awq310 21084313 · DOI
  61. Kobayashi Y Amaral DG. Macaque monkey retrosplenial cortex: II. Cortical afferents. J Comp Neurol 2003; 466: 48 – 79. doi:10.1002/cne.10883 14515240 · DOI
  62. Kobayashi Y Amaral D. Macaque monkey retrosplenial cortex: III. Cortical efferents. J Comp Neurol 2007; 502: 810 – 33. doi:10.1002/cne.21346 17436282 · DOI
  63. Lambon Ralph MA Patterson K Graham N Dawson K Hodges JR. Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: a cross-sectional and longitudinal study of 55 cases. Brain 2003; 126: 2350 – 62. doi:10.1093/brain/awg236 12876147 · DOI
  64. Laxton AW Tang-Wai DF McAndrews MP Zumsteg D Wennberg R Keren R,. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010; 68: 521 – 34. doi:10.1002/ana.22089 20687206 · DOI
  65. Lee GJ Lu PH Medina LD Rodriguez-Agudelo Y Melchor S Coppola G,. Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer’s disease mutations. J Neurol Neurosurg Psychiatry 2013; 84: 154 – 62 doi:10.1136/jnnp-2011-302087 23085935 PMC3779052 · DOI
  66. Li W Antuono PG Xie C Chen G Jones JL Ward BD,. Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOE4 carriers. Cortex 2014; 57: 167 – 76. doi:10.1016/j.cortex.2014.04.006 24905971 PMC4448757 · DOI
  67. Maguire EA. The retrosplenial contribution to human navigation: a review of lesion and neuroimaging findings. Scand J Psychol 2001; 42: 225 – 38. 11501737
  68. Mahoney CJ Beck J Rohrer JD Lashley T Mok K Shakespeare T,. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 2012; 135: 736 – 50. doi:10.1093/brain/awr361 22366791 PMC3286330 · DOI
  69. Mendez-Lopez M Arias JL Bontempi B Wolff M. Reduced cytochrome oxidase activity in the retrosplenial cortex after lesions to the anterior thalamic nuclei. Behav Brain Res 2013; 250: 264 – 73. doi:10.1016/j.bbr.2013.04.052 23660649 · DOI
  70. Metzler-Baddeley C Hunt S Jones DK Leemans A Aggleton JP O’Sullivan MJ. Temporal association tracts and the breakdown of episodic memory in mild cognitive impairment. Neurology 2012; 79: 2233 – 40. doi:10.1212/WNL.0b013e31827689e8 23175726 PMC3542350 · DOI
  71. Minoshima S Giordani B Berent S Frey KA Foster NL Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997; 42: 85 – 94. doi:10.1002/ana.410420114 9225689 · DOI · Paper page
  72. Morris R Petrides M Pandya DN. Architecture and connections of retrosplenial area 30 in the rhesus monkey (Macaca mulatta). Eur J Neurosci 1999; 11: 2506 – 18. 10383640
  73. Mufson EJ Pandya DN. Some observations on the course and composition of the cingulum bundle in the rhesus monkey. J Comp Neurol 1984; 225: 31 – 43. doi:10.1002/cne.902250105 6725639 · DOI
  74. Neave N Lloyd S Sahgal A Aggleton JP. Lack of effect of lesions in the anterior cingulate cortex and retrosplenial cortex on certain tests of spatial memory in the rat. Behav Brain Res 1994; 65: 89 – 101. doi:10.1016/0166-4328(94)90077-9 7880459 · DOI
  75. Nelson AJD Hindley EL Pearce JM Vann SD Aggleton JP. The effect of retrosplenial cortex lesions in rats on incidental and active spatial learning. Front Behav Neurosci 2015; 9: 1 – 16. doi:10.3389/fnbeh.2015.00011 25705182 PMC4319482 · DOI
  76. Nestor PJ Fryer TD Hodges JR. Declarative memory impairments in Alzheimer’s disease and semantic dementia. Neuroimage 2006; 30: 1010 – 20. doi:10.1016/j.neuroimage.2005.10.008 16300967 · DOI · Paper page
  77. Nestor PJ Fryer TD Smielewski P Hodges JR. Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 2003a; 54: 343 – 51. doi:10.1002/ana.10669 12953266 · DOI
  78. O’Dwyer L Lamberton F Matura S Tanner C Scheibe M Miller J,. Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study. PLoS One 2012; 7: e48895. doi:10.1371/journal.pone.0048895 23152815 PMC3494711 · DOI
  79. Owen AM Roberts AC Polkey CE Sahakian BJ Robbins TW. Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 1991; 29: 993 – 1006. doi:10.1016/0028-3932(91)90063-E 1762678 · DOI · Paper page
  80. Parker A Gaffan D. The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys. Neuropsychologia 1997; 35: 1093 – 102. 9256374
  81. Patel KT Stevens MC Pearlson GD Winkler AM Hawkins KA Skudlarski P,. Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers. Brain Imaging Behav 2013; 7: 60 – 7. doi:10.1007/s11682-012-9187-y 23011382 · DOI
  82. Pedro T Weiler M Yasuda CL D’Abreu A Damasceno BP Cendes F,. Volumetric brain changes in thalamus, corpus callosum and medial temporal structures: mild Alzheimer’s disease compared with amnestic mild cognitive impairment. Dement Geriatr Cogn Disord 2012; 34: 149 – 55. doi:10.1159/000342118 22986782 · DOI
  83. Pengas G Hodges JR Watson P Nestor PJ. Focal posterior cingulate atrophy in incipient Alzheimer’s disease. Neurobiol Aging 2010; 31: 25 – 33. doi:10.1016/j.neurobiolaging.2008.03.014 18455838 · DOI
  84. Perry RJ Hodges JR. Attention and executive deficits in Alzheimer’s disease: a critical review. Brain 1999; 122: 383 – 404. 10094249
  85. Perry RJ Hodges JR. Dissociation between top-down attentional control and the time course of visual attention as measured by attentional dwell time in patients with mild cognitive impairment. Eur J Neurosci 2003; 18: 221 – 6. 12887404
  86. Perry RJ Watson P Hodges JR. The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: relationship to episodic and semantic memory impairment. Neuropsychologia 2000; 38: 252 – 71. 10678692
  87. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183 – 94. doi:10.1111/j.1365-2796.2004.01388.x 15324362 · DOI · Paper page
  88. Petrella JR Sheldon FC Prince SE Calhoun VD Doraiswamy PM. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology 2011; 76: 511 – 17. doi:10.1212/WNL.0b013e31820af94e 21228297 PMC3053179 · DOI
  89. Pihlajamäki M O'Keefe K Bertram L Tanzi RE Dickerson BC Blacker D,., Evidence of altered posteromedial cortical FMRI activity in subjects at risk for Alzheimer disease. Alzheimer Dis Assoc Disord 2010; 24: 28 – 36. doi:10.1097/WAD.0b013e3181a785c9 19571734 PMC2837131 · DOI
  90. Poirier GL Amin E Good MA Aggleton JP. Early-onset dysfunction of retrosplenial cortex precedes overt amyloid plaque formation in Tg2576 mice. Neuroscience 2011; 174: 71 – 83. doi:10.1016/j.neuroscience.2010.11.025 21093545 PMC4235255 · DOI
  91. Poirier GL Shires KL Sugden D Amin E Thomas KL Carter DA,. Anterior thalamic lesions produce chronic and profuse transcriptional de-regulation in retrosplenial cortex: a model of retrosplenial hypoactivity and covert pathology. Thalamus Relat Syst 2008; 4: 59 – 77. doi:10.1017/S1472928808000368 21289865 PMC3031093 · DOI
  92. Poletti CE Creswell G. Fornix system efferent projections in the squirrel monkey: an experimental degeneration study. J Comp Neurol 1977; 175: 101 – 28. doi:10.1002/cne.901750107 407267 · DOI
  93. Prasad JA Chudasama Y. Viral tracing identifies parallel disynaptic pathways to the hippocampus. J Neurosci 2013; 33: 8494 – 503. doi:10.1523/JNEUROSCI.5072-12.2013 23658186 PMC6619633 · DOI
  94. Reinvang I Grambaite R Espeseth T. Executive dysfunction in MCI: subtype or early Symptom. Int J Alzheimers Dis 2012; 2012: 1 – 8. doi:10.1155/2012/936272 PMC3369514 22693679 · DOI
  95. Romberg C Horner AE Bussey TJ Saksida LM. A touch screen-automated cognitive test battery reveals impaired attention, memory abnormalities, and increased response inhibition in the TgCRND8 mouse model of Alzheimer’s disease. Neurobiol Aging 2013; 34: 731 – 44. doi:10.1016/j.neurobiolaging.2012.08.006 22959727 PMC3532594 · DOI
  96. Rönnbäck A Sagelius H Bergstedt KD Näslund J Westermark GT Winblad B,. Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions. Neurobiol Aging 2012; 33: 831.e11 – 19. doi:10.1016/j.neurobiolaging.2011.07.012 21880397 · DOI · Paper page
  97. Rüb U Stratmann K Heinsen H Del Turco D Ghebremedhin E Seidel K,. Hierarchical distribution of the tau cytoskeletal pathology in the thalamus of Alzheimer’s disease patients. J Alzheimers Dis 2015; 49: 905 – 15. doi:10.3233/JAD150639 26519431 · DOI
  98. Rushworth MF Paus T Sipila PK. Attention systems and the organization of the human parietal cortex. J Neurosci 2001; 21: 5262 – 71. 11438601 PMC6762864
  99. Ryan NS Keihaninejad S Shakespeare TJ Lehmann M Crutch SJ Malone IB,. Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease. Brain 2013; 136: 1399 – 414. doi:10.1093/brain/awt065 23539189 PMC3634199 · DOI · Paper page
  100. Sarazin M Berr C De Rotrou J Fabrigoule C Pasquier F Legrain S,. Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study. Neurology 2007; 69: 1859 – 67. doi:10.1212/01.wnl.0000279336.36610.f7 17984454 · DOI
  101. Scahill RI Schott JM Stevens JM Rossor MN Fox NC. Mapping the evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci USA 2002; 99: 4703 – 7. doi:10.1073/pnas.052587399 11930016 PMC123711 · DOI
  102. Smith GS Laxton AW Tang-Wai DF McAndrews MP Diaconescu AO Workman CI,. Increased Cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. Arch Neurol 2012; 69: 1141 – 8. doi:10.1001/archneurol.2012.590 22566505 · DOI
  103. Sorg C Riedl V Muhlau M Calhoun VD Eichele T Laer L,. Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2007; 104: 18760 – 5. doi:10.1073/pnas.0708803104 18003904 PMC2141850 · DOI · Paper page
  104. Squire LR Stark CEL Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004; 27: 279 – 306. doi:10.1146/annurev.neuro.27.070203.144130 15217334 · DOI · Paper page
  105. Swartz RH Black SE. Anterior-medial thalamic lesions in dementia: frequent, and volume dependently associated with sudden cognitive decline. J Neurol Neurosurg Psychiatry 2006; 77: 1307 – 12. doi:10.1136/jnnp.2006.091561 16868066 PMC2077421 · DOI
  106. Sweeney-Reed CM Zaehle T Voges J Schmitt FC Buentjen L Kopitzki K,. Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation. Elife 2014; 3: e05352. doi:10.7554/eLife.05352 25535839 PMC4302268 · DOI
  107. Sweeney-Reed CM Zaehle T Voges J Schmitt FC Buentjen L Kopitzki K,. Thalamic theta phase alignment predicts human memory formation and anterior thalamic cross-frequency coupling. Elife 2015; 4: doi:10.7554/eLife.07578 PMC4459033 25993559 · DOI
  108. Taber KH Wen C Khan A Hurley RA. The limbic thalamus. J Neuropsychiatry Clin Neurosci 2004; 16: 127 – 132. 15260362
  109. Tan RH Wong S Hodges JR Halliday GM Hornberger M. Retrosplenial cortex (BA 29) volumes in behavioral variant frontotemporal dementia and alzheimer’s disease. Dement Geriatr Cogn Disord 2013; 35: 177 – 82. doi:10.1159/000346392 23406695 · DOI
  110. Tan RH Wong S Kril JJ Piguet O Hornberger M Hodges JR,. Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia. Brain 2014; 137: 2065 – 76. doi:10.1093/brain/awu118 24844729 · DOI
  111. Toda H Hamani C Fawcett AP Hutchison WD Lozano AM. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg 2008; 108: 132 – 8. doi:10.3171/JNS/2008/108/01/0132 18173322 · DOI
  112. Torso M Serra L Giulietti G Spanò B Tuzzi E Koch G,. Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer’s disease. PLoS One 2015; 10: e0124998. doi:10.1371/journal.pone.0124998 25932637 PMC4416903 · DOI
  113. Tsivilis D Vann SD Denby C Roberts N Mayes AR Montaldi D,. A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory. Nat Neurosci 2008; 11: 834 – 42. doi:10.1038/nn.2149 18552840 · DOI
  114. Tu S Wong S Hodges JR Irish M Piguet O Hornberger M. Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia. Cortex 2015; 67: 83 – 94. doi:10.1016/j.cortex.2015.03.016 25913063 · DOI
  115. Van der Werf YD Scheltens P Lindeboom J Witter MP Uylings HBM Jolles J. Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 2003; 41: 1330 – 44. 12757906
  116. Vann SD. Dismantling the Papez circuit for memory in rats. Elife 2013; 2: e00736. doi:10.7554/eLife.00736 23805381 PMC3691571 · DOI
  117. Vann SD Aggleton JP. Evidence of a spatial encoding deficit in rats with lesions of the mammillary bodies or mammillothalamic tract. J Neurosci 2003; 23: 3506 – 14. doi:23/8/3506 [pii] 12716960 PMC6742300
  118. Vann SD Saunders RC Aggleton JP. Distinct, parallel pathways link the medial mammillary bodies to the anterior thalamus in macaque monkeys. Eur J Neurosci 2007; 26: 1575 – 86. doi:10.1111/j.1460-9568.2007.05773.x 17880392 · DOI
  119. Vogt BA Pandya DN Rosene DL. Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents. J Comp Neurol 1987; 262: 256 – 70. doi:10.1002/cne.902620207 3624554 · DOI · Paper page
  120. Wang Y Risacher SL West JD McDonald BC Magee TR Farlow MR,. Altered default mode network connectivity in older adultswith cognitive complaints and amnestic mild cognitive impairment. J Alzheimers Dis 2013; 35: 751 – 60. doi:10.3233/JAD-130080 23481685 PMC3962306 · DOI
  121. Wang Z Jia X Liang P Qi Z Yang Y Zhou W,. Changes in thalamus connectivity in mild cognitive impairment: evidence from resting state fMRI. Eur J Radiol 2012; 81: 277 – 85. doi:10.1016/j.ejrad.2010.12.044 21273022 · DOI
  122. Warburton EC Baird A Morgan A Muir JL Aggleton JP. The conjoint importance of the hippocampus and anterior thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat. J Neurosci 2001; 21: 7323 – 30. 11549742 PMC6762976
  123. Whitwell JL Weigand SD Boeve BF Senjem ML Gunter JL DeJesus-Hernandez M,. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012; 135: 794 – 806. doi:10.1093/brain/aws001 22366795 PMC3286334 · DOI · Paper page
  124. WHO. Dementia. A public health priority. Geneva, Switzerland: WHO Press; 2012.
  125. Wilcock DM Lewis MR Van Nostrand WE Davis J Previti ML Gharkholonarehe N,. Progression of amyloid pathology to Alzheimer’s disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci 2008; 28: 1537 – 45. doi:10.1523/JNEUROSCI.5066-07.2008 18272675 PMC2621082 · DOI
  126. Wright NF Vann SD Aggleton JP Nelson AJD. A critical role for the anterior thalamus in directing attention to task-relevant stimuli. J Neurosci 2015; 35: 5480 – 8. doi:10.1523/JNEUROSCI.4945-14.2015 25855166 PMC4388916 · DOI
  127. Wright NF Vann SD Erichsen JT O’Mara SM Aggleton JP. Segregation of parallel inputs to the anteromedial and anteroventral thalamic nuclei of the rat. J Comp Neurol 2013; 521: 2966 – 86. doi:10.1002/cne.23325 23504917 PMC4299679 · DOI
  128. Xiao D Barbas H. Pathways for emotions and memory I. Input and output zones linking the anterior thalamic nuclei with prefrontal cortices in the rhesus monkey. Thalamus Relat Syst 2002a; 2: 21. doi:10.1017/S1472928802000316 · DOI
  129. Xiao D Barbas H. Pathways for emotions and memory II. Afferent input to the anterior thalamic nuclei from prefrontal, temporal, hypothalamic areas and the basal ganglia in the rhesus monkey. Thalamus Relat Syst 2002b; 2: 33. doi:10.1017/S1472928802000304 · DOI
  130. Xu W Südhof TC. A neural circuit for memory specificity and generalization. Science 2013; 339: 1290 – 5. doi:10.1126/science.1229534 23493706 PMC3651700 · DOI · Paper page
  131. Xuereb JH Perry RH Candy JM Perry EK Marshall E Bonham JR. Nerve cell loss in the thalamus in Alzheimer’s disease and Parkinson's disease. Brain 1991; 114: 1363 – 79. 2065255
  132. Yi HA Moller C Dieleman N Bouwman FH Barkhof F Scheltens P,. Relation between subcortical grey matter atrophy and conversion from mild cognitive impairment to Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2015; doi:10.1136/jnnp-2014-309105 25904810 · DOI
  133. Zarei M Patenaude B Damoiseaux J Morgese C Smith S Matthews PM,. Combining shape and connectivity analysis: an MRI study of thalamic degeneration in Alzheimer’s disease. Neuroimage 2010; 49: 1 – 8. doi:10.1016/j.neuroimage.2009.09.001 19744568 · DOI
  134. Zhang C Hu WH Wu DL Zhang K Zhang JG. Behavioral effects of deep brain stimulation of the anterior nucleus of thalamus, entorhinal cortex and fornix in a rat model of Alzheimer’s disease. Chin Med J (Engl) 2015; 128: 1190 – 5. doi:10.4103/0366-6999.156114 25947402 PMC4831546 · DOI · Paper page
  135. Zhou B Liu Y Zhang Z An N Yao H Wang P,. Impaired functional connectivity of the thalamus in Alzheimer’s disease and mild cognitive impairment: a resting-state fMRI study. Curr Alzheimer Res 2013; 10: 754 – 66. 23905993

Cited by

Sorted by citations

Authors
Aggleton, J. P., Pralus, A., Nelson, A. J. D., & Hornberger, M.
Affiliations
  • Cardiff University (GB)
  • École Normale Supérieure de Lyon (FR)
  • University of East Anglia (GB)
Corresponding author
Aggleton, John P.
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2016-04-28
Volume
139
Issue
7
Pages
1877-1890
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/aww083
PMC
PMC4939698
OpenAlex
W2342702273
Cited by
378
References
15
Citations by year
2026: 27 · 2025: 29 · 2024: 48 · 2023: 50 · 2022: 50 · 2021: 53 · 2020: 41 · 2019: 25 · 2018: 30 · 2017: 20 · 2016: 5
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Brain (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
Wellcome Trust (103722, 103722/Z/14/Z)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, Papez circuit, anterior thalamic nuclei, medial temporal lobe, retrosplenial cortex, prodromal Alzheimer's disease, hippocampus, at-risk individuals, transgenic animal models, postmortem studies, non-invasive imaging
MeSH terms
Alzheimer Disease, Animals, Humans, Limbic System, Thalamus, Memory, Episodic

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