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So what if tangles precede plaques?
Neurobiology of Aging 25 (2004) 721–723
Commentary
So what if tangles precede plaques? J.L. Price∗ , J.C. Morris Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA Received 1 December 2003; accepted 10 December 2003
As proposed by Hardy and Higgins in 1992 [8], the amyloid hypothesis had two tenets. First, that deposition of -amyloid (A) is the causative agent of Alzheimer’s disease (AD) pathology, and secondly that other lesions (tangles, dystrophic neurites, synaptic and cell loss, vascular degeneration) follow directly from this deposition. In their paper analyzing early formation of amyloid plaques and neurofibrillary tangles, Schonheit et al. aim to refute the second tenet, arguing that tangles form without or prior to the presence of plaques, and therefore that A cannot be the causative agent for neurofibrillary lesions. As discussed below, their argument is consistent with earlier observations that at least the initial formation of tangles is independent of A. On the other hand, the first tenet of the amyloid hypothesis is now supported so strongly by several lines of evidence that it is difficult to refute it. The challenge is how to reconcile these seemingly contradictory conclusions. Probably, the most compelling evidence that A is the causative agent of AD comes from observations on genetic mutations or other conditions that cause familial forms of AD, all of which produce an elevation in A or its more toxic form, A1–42 [21,22]. These mutations occur directly in the gene for amyloid precursor protein (APP), and produce excess A, or occur in the genes for the Presenilin proteins, which form an important part of the ␥-secretase complex that cuts APP to liberate A. Down’s Syndrome, with triplication of chromosome 21, also results almost invariably in AD, beginning at ages at which AD is extremely rare. Because the gene for APP is on the chromosome 21, an excess amount of A is generated. Amyloid plaques develop in Down’s Syndrome brains at about the age of 20–30 years, and large numbers of tangles appear in these cases during the third to fifth decades of life [9,11,12,26]. Although these genetic conditions account for only a small fraction of the total number of AD cases, the associated pattern of
∗
Corresponding author. Tel.: +1-314-362-3587; fax: +1-314-747-5584. E-mail address: [email protected] (J.L. Price).
0197-4580/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2003.12.017
neuropathological lesions is essentially the same as that in “sporadic AD”. In addition, widespread deposition of A in plaques provides the best neuropathological distinction of aging from AD [14,15,25]. Although early studies suggested that both plaques and tangles occur during aging, and only the number of the lesions distinguish aging from AD (e.g. Refs. [3,10,24]), it is likely that those studies included cases that would now be recognized as mild AD [14]. In particular, the earlier studies examined brain tissue from institutionalized patients, and used relatively insensitive criteria to diagnose dementia. Subsequent studies on more carefully assessed cases have indicated that while even very mild AD cases have widespread and substantial numbers of plaques, most non-demented cases do not [14,25]. Those non-demented cases with large numbers of plaques appear to represent the “preclinical” or “pre-symptomatic” stage of AD, in which the underlying disease process has begun, but has not yet produced sufficient deficit to be clinically or psychometrically detectable [5,19,20]. Taken together with the genetic data, this implies that A is the critical driving factor in the initiation of AD. Still, as Schonheit et al. point out, in its original form the amyloid hypothesis implies that plaques should develop before tangles. Several observations, including those reported by Schonheit et al., indicate that this is not correct, except in the special case of Down’s Syndrome. In our studies, tangles were found in the entorhinal cortex and field CA1 of the hippocampus in all non-demented aging cases over about 60 years of age, but cases without plaques were found to almost 90 years of age [17,19]. In their study of 2661 cases, Braak and Braak [2] found that 98% of cases aged 76–95 years had tangles and other neurofibrillary changes, at least in the entorhinal region, while only 70% of these cases had any plaques. Post hoc analyses of these data in commentaries on the Braak and Braak paper indicated that the initial development of tangles (neurofibrillary stages I and II) precedes the development of amyloid plaques by at least two decades (Silverman et al. [23]; Duyckaerts and Hauw [4]).
722
J.L. Price, J.C. Morris / Neurobiology of Aging 25 (2004) 721–723
The problem, then, is how to reconcile the very strong evidence that A is the causative agent in AD, with the equally strong evidence that formation of tangles precedes deposition of A into plaques. Schonheit et al., suggest two interpretations to their observations: either tangles precede plaques and by implication play a causative role in plaque formation in contradiction to the amyloid hypothesis, or the two lesions are independent. In the discussion, however, they support a further hypothesis we suggested during the past decade [18,19]. That is, while the initial neurofibrillary changes in tangles and elsewhere are independent of A, this process is accelerated by the presence of A, either in plaques or in a diffusible form (possibly oligomers of A). Tangles form during aging with or without plaques, and their density increases exponentially with increasing age [1,18,19]. In the absence of A plaques, however, the neurofibrillary changes are relatively slow, and are largely restricted to medial temporal lobe structures. Further, the earliest deposition of A in plaques appears to occur in the temporal or frontal cortex, spatially separate from the tangles in the medial temporal lobe. In preclinical AD cases, which have substantial number of plaques but do not yet show any cognitive decline, there is evidence that the rate of increase of tangles with age is greater than in cases with few or no plaques [19]. Perhaps the most compelling observation, however, is that dystrophic neurites, with the same paired helical filaments as in tangles, form within the confines of A plaques (i.e. in neuritic plaques). This implies that the high concentration of A in plaques has induced the neurofibrillary changes in dystrophic neurites.
Aging
Indeed, the appearance of neuritic plaques in the neocortex, indicating the conjunction of both A and neurofibrillary lesions, is the key neuropathological indication of AD in both the CERAD and NIA-Reagan criteria [13,16]. Although A, either in plaques or as diffusible oligomers, may be the initiating and driving factor in AD, tangles show a much closer spatial and temporal correlation to cell loss. This is especially striking in the best characterized examples of cell death in the early stage of AD, in layers II and IV of the entorhinal cortex, and hippocampal field CA1, where substantial numbers of tangles develop in precisely the same neurons that slightly later show extensive degeneration [6,20]. In the superior temporal cortex, plaques develop early in AD, but both tangles or neuronal degeneration develop together in more severe stages of AD [7]. This suggests that tangles are involved in the process of cell degeneration, either as a causative factor, or as a parallel marker of the process of degeneration. Cumulative cell degeneration far exceeds the number of tangles present at a given time (i.e. at the time of death), however, so either tangles disappear, or not all cell degeneration is related to neurofibrillary lesions. We interpret this evidence, taken together, to indicate that slow accumulation of tangles is ubiquitous during aging, and initially is independent of A (Fig. 1). In the absence of disease (i.e. AD), however, tangles and other neurofibrillary changes remain largely limited to medial temporal lobe structures. With the appearance of A and its deposition in plaques in the early stages of AD, the formation of neurofibrillary lesions, including both tangles and dystrophic
Severe AD
Early AD Pre-Clinical
Very Mild Dementia
1st Clinical Detection
CDR = 0
Slow changes in the configuration and phosphorylation of Tau with increasing Age produce Tangles in vulnerable Limbic Areas. Slow extracellular aggregation of Aß Fibrils produces patches of diffuse Plaques in Neocortex. (Absent through 9th Decade in some Individuals.)
CDR = 0.5
Increasing deposition of Aß in numerous Plaques throughout Neocortical Areas. Formation of neurofibrillary Lesions (Tangles and dystrophic Neurites) accelerate, possibly due to interaction with Aß.
CDR = 1, 2, 3
Continued effect of Aß greatly increases neurofibrillary Lesions and neuronal Dysfunction/Death throughout Cerebral Cortex.
Cell Death associated with Tangles and dystrophic Neurites in Limbic Areas.
Fig. 1. Diagram of neuropathological changes related to aging and the progression into early and late AD, to illustrate the proposed relation between A and neurofibrillary lesions. During aging, tangles and other neurofibrillary changes accumulate slowly in vulnerable limbic areas. In many but not all individuals, diffuse A plaques begin to accumulate independently in the neocortex. During the preclinical stage of early AD, before clinical detection is possible, much more widespread deposition of A in plaques occurs in the neocortex, and is postulated to induce an acceleration in neurofibrillary lesions. Subsequently, the neurofibrillary lesions are associated with neuronal death in limbic areas, at the same time as dementia become clinically detectable. Further progress of the disease produces widespread neurofibrillary lesions and neuronal degeneration throughout the cerebral cortex.
J.L. Price, J.C. Morris / Neurobiology of Aging 25 (2004) 721–723
neurites, is accelerated and spreads to involve the neocortex. Because the neurofibrillary lesions reflect synaptic and neuronal loss, they are better correlates of dementia severity than A plaque density. However, the neurofibrillary lesions in the neocortex occur subsequent to the appearance of A plaques, suggesting that A deposition manifests the causative process of AD. In our view the amyloid hypothesis remains very tenable. References [1] Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 1992;42:1681–8. [2] Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:351–7. [3] Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 1988;38:1682–7. [4] Duyckaerts C, Hauw JJ. Prevalence; incidence and duration of Braak’s stages in the general population: can we know? Neurobiol Aging 1997;18:362–9. [5] Goldman WP, Price JL, Storandt M, Grant EA, McKeel Jr DW, Rubin EH, et al. Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Neurology 2001;56:361–7. [6] Gomez-Isla T, Price JL, McKeel DW, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons distinguishes very mild Alzheimer’s disease from nondemented aging. J Neurosci 1996;16:4491–500. [7] Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1997;41:17–24. [8] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–5. [9] Hof PR, Bouras C, Perl DP, Sparks DL, Mehta N, Morrison JH. Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Quantitative regional analysis and comparison with Alzheimer’s disease. Arch Neurol 1995;52:379–91. [10] Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 1988;23:138–44. [11] Mann DM, Yates PO, Marcyniuk B, Ravindra CR. The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 1986;12:447–57.
723
[12] Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 1989;89:169–79. [13] Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479– 86. [14] Morris JC, Storandt M, McKeel DW, Rubin EH, Price JL, Grant EA, et al. Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 1996;46:707–19. [15] Morris JC, Price JL. Pathological correlates of nondemented aging mild cognitive impairment and early stage Alzheimer’s disease. J Mol Neursoci 2001;17:101–18. [16] National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging 1997;18:S1–2. [17] Price JL, Davis PB, Morris JC, White DL. The distribution of tangles; plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 1991;12:295– 312. [18] Price JL. Tangles and plaques in healthy aging and Alzheimer’s disease. Independence or interaction? Semin Neurosci 1994;6:395– 402. [19] Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 1999;45:13290– 5. [20] Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 2001;58:1395–402. [21] Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci 2000;924:17–25. [22] Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–66. [23] Silverman W, Wisniewski HM, Bobinski M, Wegiel J. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:377–9. [24] Tomlinson BE, Blessed G, Roth M. Observations on the brains of non-demented old people. J Neurol Sci 1968;7:331–56. [25] Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol Aging 1996;17:365– 71. [26] Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985;17:278–82.
Commentary
So what if tangles precede plaques? J.L. Price∗ , J.C. Morris Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA Received 1 December 2003; accepted 10 December 2003
As proposed by Hardy and Higgins in 1992 [8], the amyloid hypothesis had two tenets. First, that deposition of -amyloid (A) is the causative agent of Alzheimer’s disease (AD) pathology, and secondly that other lesions (tangles, dystrophic neurites, synaptic and cell loss, vascular degeneration) follow directly from this deposition. In their paper analyzing early formation of amyloid plaques and neurofibrillary tangles, Schonheit et al. aim to refute the second tenet, arguing that tangles form without or prior to the presence of plaques, and therefore that A cannot be the causative agent for neurofibrillary lesions. As discussed below, their argument is consistent with earlier observations that at least the initial formation of tangles is independent of A. On the other hand, the first tenet of the amyloid hypothesis is now supported so strongly by several lines of evidence that it is difficult to refute it. The challenge is how to reconcile these seemingly contradictory conclusions. Probably, the most compelling evidence that A is the causative agent of AD comes from observations on genetic mutations or other conditions that cause familial forms of AD, all of which produce an elevation in A or its more toxic form, A1–42 [21,22]. These mutations occur directly in the gene for amyloid precursor protein (APP), and produce excess A, or occur in the genes for the Presenilin proteins, which form an important part of the ␥-secretase complex that cuts APP to liberate A. Down’s Syndrome, with triplication of chromosome 21, also results almost invariably in AD, beginning at ages at which AD is extremely rare. Because the gene for APP is on the chromosome 21, an excess amount of A is generated. Amyloid plaques develop in Down’s Syndrome brains at about the age of 20–30 years, and large numbers of tangles appear in these cases during the third to fifth decades of life [9,11,12,26]. Although these genetic conditions account for only a small fraction of the total number of AD cases, the associated pattern of
∗
Corresponding author. Tel.: +1-314-362-3587; fax: +1-314-747-5584. E-mail address: [email protected] (J.L. Price).
0197-4580/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2003.12.017
neuropathological lesions is essentially the same as that in “sporadic AD”. In addition, widespread deposition of A in plaques provides the best neuropathological distinction of aging from AD [14,15,25]. Although early studies suggested that both plaques and tangles occur during aging, and only the number of the lesions distinguish aging from AD (e.g. Refs. [3,10,24]), it is likely that those studies included cases that would now be recognized as mild AD [14]. In particular, the earlier studies examined brain tissue from institutionalized patients, and used relatively insensitive criteria to diagnose dementia. Subsequent studies on more carefully assessed cases have indicated that while even very mild AD cases have widespread and substantial numbers of plaques, most non-demented cases do not [14,25]. Those non-demented cases with large numbers of plaques appear to represent the “preclinical” or “pre-symptomatic” stage of AD, in which the underlying disease process has begun, but has not yet produced sufficient deficit to be clinically or psychometrically detectable [5,19,20]. Taken together with the genetic data, this implies that A is the critical driving factor in the initiation of AD. Still, as Schonheit et al. point out, in its original form the amyloid hypothesis implies that plaques should develop before tangles. Several observations, including those reported by Schonheit et al., indicate that this is not correct, except in the special case of Down’s Syndrome. In our studies, tangles were found in the entorhinal cortex and field CA1 of the hippocampus in all non-demented aging cases over about 60 years of age, but cases without plaques were found to almost 90 years of age [17,19]. In their study of 2661 cases, Braak and Braak [2] found that 98% of cases aged 76–95 years had tangles and other neurofibrillary changes, at least in the entorhinal region, while only 70% of these cases had any plaques. Post hoc analyses of these data in commentaries on the Braak and Braak paper indicated that the initial development of tangles (neurofibrillary stages I and II) precedes the development of amyloid plaques by at least two decades (Silverman et al. [23]; Duyckaerts and Hauw [4]).
722
J.L. Price, J.C. Morris / Neurobiology of Aging 25 (2004) 721–723
The problem, then, is how to reconcile the very strong evidence that A is the causative agent in AD, with the equally strong evidence that formation of tangles precedes deposition of A into plaques. Schonheit et al., suggest two interpretations to their observations: either tangles precede plaques and by implication play a causative role in plaque formation in contradiction to the amyloid hypothesis, or the two lesions are independent. In the discussion, however, they support a further hypothesis we suggested during the past decade [18,19]. That is, while the initial neurofibrillary changes in tangles and elsewhere are independent of A, this process is accelerated by the presence of A, either in plaques or in a diffusible form (possibly oligomers of A). Tangles form during aging with or without plaques, and their density increases exponentially with increasing age [1,18,19]. In the absence of A plaques, however, the neurofibrillary changes are relatively slow, and are largely restricted to medial temporal lobe structures. Further, the earliest deposition of A in plaques appears to occur in the temporal or frontal cortex, spatially separate from the tangles in the medial temporal lobe. In preclinical AD cases, which have substantial number of plaques but do not yet show any cognitive decline, there is evidence that the rate of increase of tangles with age is greater than in cases with few or no plaques [19]. Perhaps the most compelling observation, however, is that dystrophic neurites, with the same paired helical filaments as in tangles, form within the confines of A plaques (i.e. in neuritic plaques). This implies that the high concentration of A in plaques has induced the neurofibrillary changes in dystrophic neurites.
Aging
Indeed, the appearance of neuritic plaques in the neocortex, indicating the conjunction of both A and neurofibrillary lesions, is the key neuropathological indication of AD in both the CERAD and NIA-Reagan criteria [13,16]. Although A, either in plaques or as diffusible oligomers, may be the initiating and driving factor in AD, tangles show a much closer spatial and temporal correlation to cell loss. This is especially striking in the best characterized examples of cell death in the early stage of AD, in layers II and IV of the entorhinal cortex, and hippocampal field CA1, where substantial numbers of tangles develop in precisely the same neurons that slightly later show extensive degeneration [6,20]. In the superior temporal cortex, plaques develop early in AD, but both tangles or neuronal degeneration develop together in more severe stages of AD [7]. This suggests that tangles are involved in the process of cell degeneration, either as a causative factor, or as a parallel marker of the process of degeneration. Cumulative cell degeneration far exceeds the number of tangles present at a given time (i.e. at the time of death), however, so either tangles disappear, or not all cell degeneration is related to neurofibrillary lesions. We interpret this evidence, taken together, to indicate that slow accumulation of tangles is ubiquitous during aging, and initially is independent of A (Fig. 1). In the absence of disease (i.e. AD), however, tangles and other neurofibrillary changes remain largely limited to medial temporal lobe structures. With the appearance of A and its deposition in plaques in the early stages of AD, the formation of neurofibrillary lesions, including both tangles and dystrophic
Severe AD
Early AD Pre-Clinical
Very Mild Dementia
1st Clinical Detection
CDR = 0
Slow changes in the configuration and phosphorylation of Tau with increasing Age produce Tangles in vulnerable Limbic Areas. Slow extracellular aggregation of Aß Fibrils produces patches of diffuse Plaques in Neocortex. (Absent through 9th Decade in some Individuals.)
CDR = 0.5
Increasing deposition of Aß in numerous Plaques throughout Neocortical Areas. Formation of neurofibrillary Lesions (Tangles and dystrophic Neurites) accelerate, possibly due to interaction with Aß.
CDR = 1, 2, 3
Continued effect of Aß greatly increases neurofibrillary Lesions and neuronal Dysfunction/Death throughout Cerebral Cortex.
Cell Death associated with Tangles and dystrophic Neurites in Limbic Areas.
Fig. 1. Diagram of neuropathological changes related to aging and the progression into early and late AD, to illustrate the proposed relation between A and neurofibrillary lesions. During aging, tangles and other neurofibrillary changes accumulate slowly in vulnerable limbic areas. In many but not all individuals, diffuse A plaques begin to accumulate independently in the neocortex. During the preclinical stage of early AD, before clinical detection is possible, much more widespread deposition of A in plaques occurs in the neocortex, and is postulated to induce an acceleration in neurofibrillary lesions. Subsequently, the neurofibrillary lesions are associated with neuronal death in limbic areas, at the same time as dementia become clinically detectable. Further progress of the disease produces widespread neurofibrillary lesions and neuronal degeneration throughout the cerebral cortex.
J.L. Price, J.C. Morris / Neurobiology of Aging 25 (2004) 721–723
neurites, is accelerated and spreads to involve the neocortex. Because the neurofibrillary lesions reflect synaptic and neuronal loss, they are better correlates of dementia severity than A plaque density. However, the neurofibrillary lesions in the neocortex occur subsequent to the appearance of A plaques, suggesting that A deposition manifests the causative process of AD. In our view the amyloid hypothesis remains very tenable. References [1] Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 1992;42:1681–8. [2] Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:351–7. [3] Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 1988;38:1682–7. [4] Duyckaerts C, Hauw JJ. Prevalence; incidence and duration of Braak’s stages in the general population: can we know? Neurobiol Aging 1997;18:362–9. [5] Goldman WP, Price JL, Storandt M, Grant EA, McKeel Jr DW, Rubin EH, et al. Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Neurology 2001;56:361–7. [6] Gomez-Isla T, Price JL, McKeel DW, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons distinguishes very mild Alzheimer’s disease from nondemented aging. J Neurosci 1996;16:4491–500. [7] Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1997;41:17–24. [8] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–5. [9] Hof PR, Bouras C, Perl DP, Sparks DL, Mehta N, Morrison JH. Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Quantitative regional analysis and comparison with Alzheimer’s disease. Arch Neurol 1995;52:379–91. [10] Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 1988;23:138–44. [11] Mann DM, Yates PO, Marcyniuk B, Ravindra CR. The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 1986;12:447–57.
723
[12] Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 1989;89:169–79. [13] Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479– 86. [14] Morris JC, Storandt M, McKeel DW, Rubin EH, Price JL, Grant EA, et al. Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 1996;46:707–19. [15] Morris JC, Price JL. Pathological correlates of nondemented aging mild cognitive impairment and early stage Alzheimer’s disease. J Mol Neursoci 2001;17:101–18. [16] National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging 1997;18:S1–2. [17] Price JL, Davis PB, Morris JC, White DL. The distribution of tangles; plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 1991;12:295– 312. [18] Price JL. Tangles and plaques in healthy aging and Alzheimer’s disease. Independence or interaction? Semin Neurosci 1994;6:395– 402. [19] Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 1999;45:13290– 5. [20] Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 2001;58:1395–402. [21] Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci 2000;924:17–25. [22] Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–66. [23] Silverman W, Wisniewski HM, Bobinski M, Wegiel J. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:377–9. [24] Tomlinson BE, Blessed G, Roth M. Observations on the brains of non-demented old people. J Neurol Sci 1968;7:331–56. [25] Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol Aging 1996;17:365– 71. [26] Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985;17:278–82.