Staging of Alzheimer-Related Cortical Destruction
Abstract
The gradual intraneuronal accumulation of an insoluble fibrous material which partly consists of abnormally phosphorylated tau protein (neurofibrillary change) represents an important neuropathological hallmark of Alzheimer’s disease. Neurofibrillary tangles and neuropil threads formed from this material develop in only a few types of cortical pyramidal cells. The first changes are seen in the entorhinal cortex. The destructive process then spreads into the hippocampal formation and eventually encroaches upon the isocortex. This sequence of events permits the distinction of six stages with a progressive increase in the severity of cortical destruction. The entorhinal region serves as an important interface between the isocortex and hippocampus. This interface function is markedly impaired due to the early deterioration of the entorhinal cortex. Severe entorhinal involvement is considered to represent the morphological counterpart of clinically incipient Alzheimer’s disease. Similar changes are found in mentally impaired individuals suffering from Parkinson’s disease or progressive supranuclear palsy.
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The pattern of NFT development across the clinical spectrum of disease has been integrated in Braak neuropathologic staging.
“On the basis of the review of an enormous sample of cross-sectional autopsy data, the pattern of NFT development across the clinical spectrum of disease has been integrated in Braak neuropathologic staging (60, 298, 299).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [299]
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“Examination (MMSE) score; no Braak neurofibrillary staging [5]; no Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) [20] neuritic plaques data;”
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“The entorhinal cortex and hippocampus were the regions chosen because of the abundance of evidence implicating these regions in the earliest stages of disease [6,7,10,22].”
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“The deficit sequence also matches the trajectory of neurofibrillary tangle distribution observed post mortem, in patients with increasing dementia severity at death (Braak and Braak, 1997).”
BackgroundHypocretin (orexin) loss in Alzheimer's disease
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“For all cases, the clinical diagnosis was verified by a systematic neuropathological examination according to van de Nes et al. and Braak et al. (Braak et al., 1993; van de Nes et al., 1998).”
MethodNeuroimaging of Healthy Cognitive Aging
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“7, 50) 0 (0, 0) 0 (0, 25) 0 (0, 0) Hippocampal sclerosis 2, n (%) 4 (27) 4 (12) 2 (22) 4 (19)”
Temporal Specification and Bilaterality of Human Neocortical Topographic Gene Expression
Pletikos, M., Sousa, A. M. M., Sedmak, G., Meyer, K. A., Zhu, Y., Cheng, F., Li, M., Kawasawa, Y. I., & Šestan, N. (2014) · Neuron · doi:10.1016/j.neuron.2013.11.018 · Cited by 228 · see citing works
“Moreover, the progression of certain neuropathologies follows a stereotypic areal pattern (Braak et al., 1993), indicating that the mechanisms involved in patterning and asymmetry may play a role in the manifestation of disease.”
Guglielmotto, M., Aragno, M., Autelli, R., Giliberto, L., Novo, E., Colombatto, S., Danni, O., Parola, M., Smith, M. A., Perry, G. L., et al. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05858.x · Cited by 243 · see citing works
“The disease is pathologically characterized by the formation in the brain of intracellular neurofibrillary tangles and extracellular amyloid deposits (Braak et al. 1993; Jellinger 1998).”
BackgroundFleisher, A., Chen, K., Quiroz, Y. T., Jakimovich, L. J., Gomez, M. G., Langois, C. M., Langbaum, J. B. S., Ayutyanont, N., Roontiva, A., Thiyyagura, P., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70227-2 · Cited by 242 · see citing works
Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia
Zarow, C., Vinters, H. V., Ellis, W. G., Weiner, M. W., Mungas, D., White, L., & Chui, H. C. (2005) · Annals of Neurology · doi:10.1002/ana.20503 · Cited by 241 · see citing works
Nelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Smith, C. D., Davis, D. G., Poduska, J. W., Patel, E., Mendiondo, M. S., et al. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00244.x · Cited by 239 · see citing works
“These findings are compatible with Braak staging (19, 20).”
BackgroundResultVolumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease
Mungas, D., Reed, B., Jagust, W. J., DeCarli, C. S., Mack, W. J., Kramer, J. H., Weiner, M. W., Schuff, N. W., & Chui, H. C. (2002) · Neurology · doi:10.1212/wnl.59.6.867 · Cited by 233 · see citing works
Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis
Grabrucker, S., Marizzoni, M., Silajdžić, E., Lopizzo, N., Mombelli, E., Nicolas, S., Dohm-Hansen, S., Scassellati, C., Moretti, D. V., Rosa, M., et al. (2023) · Brain · doi:10.1093/brain/awad303 · Cited by 236 · see citing works
“8 The hippocampus is also host to a population of neural stem cells, which generate new neurons throughout the lifespan in a process called adult hippocampal neurogenesis (AHN).”
Kocahan, S., & Doğan, Z. (2017) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2017.15.1.1 · Cited by 238 · see citing works
Spatially augmented LPboosting for AD classification with evaluations on the ADNI dataset
Chris Hinrichs, A., Singh, V., Mukherjee, L., Xu, G., Chung, M. K., & Johnson, S. C. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.05.056 · Cited by 226 · see citing works
“We find these results encouraging because the selected regions are all known to be affected in AD patients (Braak et al., 1993).”
Trillo, L., Das, D., Hsieh, W., Medina, B., Moghadam, S., Lin, B., Dang, V., Sanchez, M. M., Miguel, Z. D., Ashford, J. W., et al. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.05.008 · Cited by 224 · see citing works
Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease
Farfara, D., Lifshitz, V., & Frenkel, D. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00314.x · Cited by 216 · see citing works
“Intracellular abnormally phosphorylated tau and A exhibit synergistic effects that finally lead to an acceleration of neurodegenerative mechanisms involved in metabolism, cellular detoxification, mitochondrial dysfunction and energy deficiency, which result in the formation of neuritic plaques [1].”
BackgroundChoo, I. H., Lee, D. Y., Oh, J. S., Lee, J. S., Lee, D. S., Song, I. C., Youn, J. C., Kim, S. G., Kim, K. W., Jhoo, J. H., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.06.015 · Cited by 211 · see citing works
Krasuski, J., Alexander, G. E., Horwitz, B., Daly, E., Murphy, D., Rapoport, S. I., & Schapiro, M. B. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(97)00013-9 · Cited by 211 · see citing works
Trivedi, M. A., Schmitz, T. W., Ries, M. L., Torgerson, B. M., Sager, M. A., Hermann, B. P., Asthana, S., & Johnson, S. C. (2006) · BMC Medicine · doi:10.1186/1741-7015-4-1 · Cited by 210 · see citing works
“Impairment in the encoding and retrieval of episodic memories, presumably caused by neurodegeneration of the hippocampus and other medial temporal lobe (MTL) structures [6,7], is one of the earliest symptoms in AD [8].”
BackgroundEvaluation of olfactory dysfunction in neurodegenerative diseases
Barresi, M., Ciurleo, R., Giacoppo, S., Cuzzola, V. F., Celi, D., Bramanti, P., & Marino, S. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.08.028 · Cited by 205 · see citing works
“, 1993 [50]; Pearson,”
BackgroundCo-Localization of Amyloid Beta and Tau Pathology in Alzheimer's Disease Synaptosomes
Fein, J. A., Sokolow, S., Miller, C. A., Vinters, H. V., Yang, F., Cole, G. M., & Gylys, K. H. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070829 · Cited by 203 · see citing works
Temporal lobe functional activity and connectivity in young adult <i>APOE</i> ɛ4 carriers
Dennis, N. A., Browndyke, J. N., Stokes, J., Need, A., Burke, J. R., Welsh‐Bohmer, K. A., & Cabeza, R. (2010) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2009.07.003 · Cited by 201 · see citing works
“Studies of functional, structural, and behavioral differences associated with variants of the APOE genotype have focused on the MTL, based on abundant evidence identifying the MTL as the earliest site of AD-associated pathology [22].”
BackgroundBaker, J. E., Lim, Y., Pietrzak, R., Hassenstab, J. J., Snyder, P., Masters, C., & Maruff, P. (2016) · Alzheimer's & Dementia · doi:10.1016/j.dadm.2016.09.002 · Cited by 192 · see citing works
Foster, P. P., Rosenblatt, K. P., & Kuljiš, R. O. (2011) · Frontiers in Neurology · doi:10.3389/fneur.2011.00028 · Cited by 204 · see citing works
“Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events.”
BackgroundBrückner, G., Hausen, D., Härtig, W., Drlicek, M., Arendt, T., & Brauer, K. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00071-8 · Cited by 196 · see citing works
Wong, T. P., Debeir, T., Duff, K., & Cuello, A. C. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-07-02706.1999 · Cited by 196 · see citing works
“In humans, AD neurofibrillary pathology appears to commence in the entorhinal cortex, spreading into the hippocampus and isocortex (Braak et al., 1993; Braak and Braak, 1996).”
BackgroundMild Cognitive Impairment: Diagnosis, Longitudinal Course, and Emerging Treatments
Vega, J. N., & NEWHOUSE, P. A. (2014) · Current Psychiatry Reports · doi:10.1007/s11920-014-0490-8 · Cited by 196 · see citing works
Reagh, Z. M., Noche, J. A., Tustison, N. J., Delisle, D., Murray, E. A., & Yassa, M. A. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.039 · Cited by 195 · see citing works
“Given prior findings of PRC dysfunction in animal models of aging (Burke et al., 2011, 2014; Ryan et al., 2012) and AD-related pathology in the region (Braak, Braak, and Bohl, 1993; Braak and Braak, 1995; Hirni et al., 2016; Jack et al., 1997), it is interesting and Neuron.”
Cotman, C. W., & Head, E. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15413 · Cited by 188 · see citing works
“Our work and the work of others demonstrate that specific brain regions show differential accumulation of A β , paralleling some reports in the aged human brain [21, 22,67,74,90,175,199,227,228].”
Arendt, T. (2003) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2003.09.007 · Cited by 188 · see citing works
Lüth, H. J. (2004) · Cerebral Cortex · doi:10.1093/cercor/bhh123 · Cited by 186 · see citing works
“NFTs consist mainly of abnormally phosphorylated tau protein (Braak et al., 1993).”
BackgroundEarly Olfactory Involvement in Alzheimer’s Disease
Christen‐Zaech, S., Kraftsik, R., Pillevuit, O., Kiraly, M., Martins, R. N., Khalili, K., & Judith Miklossy, A. (2003) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100002389 · Cited by 184 · see citing works
Nussbaum-Krammer, C. I., Neto, M. F., Brielmann, R. M., Pedersen, J. S., & Morimoto, R. I. (2015) · Journal of Visualized Experiments · doi:10.3791/52321 · Cited by 186 · see citing works
Atrophy rates accelerate in amnestic mild cognitive impairment
Jack, C. R., Weigand, S. D., Shiung, M. M., Przybelski, S. A., O’Brien, P. C., Gunter, J. L., Knopman, D. S., Boeve, B. F., Smith, G. E., & Petersen, R. C. (2007) · Neurology · doi:10.1212/01.wnl.0000281688.77598.35 · Cited by 175 · see citing works
“Median (min, max) WAIS-R block design scaled score 7 (1, 17) 7 (4, 11) 6 (1, 17) 0.”
Muhs, A., Hickman, D. T., Pihlgren, M., Chuard, N., Giriens, V., Meerschman, C., der Auwera, I. V., LEUVEN, F. V., Sugawara, M., Weingertner, M.-C., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703137104 · Cited by 176 · see citing works
Visual-discrimination learning ability and β-amyloid accumulation in the dog
Head, E., Callahan, H., Muggenburg, B. A., Cotman, C. W., & Milgram, N. W. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(98)00084-0 · Cited by 176 · see citing works
Twenty-first century brain banking. Processing brains for research: the Columbia University methods
Vonsattel, J. P., Amaya, M. D. P., & Keller, C. E. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0311-9 · Cited by 169 · see citing works
“A brain is assigned to the category of Alzheimer disease Lewy body variant (ADLBV) if there is documented dementia, neuronal loss with neuritic plaques, and neurofibrillary tangles that occur in numbers of diagnostic significance for AD, and with cortical and subcortical Lewy bodies [19, 20].”
MethodInfluential
- Authors
- Braak, H., Braak, E., & Bohl, J.
- Affiliations
- Goethe University Frankfurt (DE)
- ORCID
- Braak, Heiko
- Venue
- European Neurology
- Publisher
- S. Karger AG
- Published
- 2008-02-12
- Volume
- 33
- Issue
- 6
- Pages
- 403-408
- ISSN
- 0014-3022 (ISSN-L)
- 1421-9913
- OpenAlex
- W2095422335
- Cited by
- 836
- References
- 0
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 29 · 2023: 34 · 2022: 38 · 2021: 32 · 2020: 35 · 2019: 33 · 2018: 30 · 2017: 40 · 2016: 35 · 2015: 47 · 2014: 36 · 2013: 39 · 2012: 35
- FWCI
- 29.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, cortical destruction, neurofibrillary tangles, tau protein, neuropil threads, entorhinal cortex, hippocampal formation, neocortex, disease staging, cortical pyramidal neurons, Parkinson's disease, progressive supranuclear palsy, neuropathology
- MeSH terms
- Aged, Alzheimer Disease, Brain Mapping, Cerebral Cortex, Dementia, Diagnosis, Differential, Hippocampus, Humans, Limbic System, Parkinson Disease, Supranuclear Palsy, Progressive, Neurites, Neurofibrillary Tangles
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