histopathology of Alzheimer's disease
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Pathology
Abnormal morphologic structures:
- neurofibrillary tangles formed from paired helical filaments of hyperphosphorylated microtubule-associated protein tau
- neuritic plaques resulting from deposition of Abeta42
- granulovacuolar degeneration
- cerebral amyloid angiopathy
- Hirano bodies
* see figure A neurofibrillary tangles & figure B neuritic plaque
Other:
- selective neuronal loss
- intraneuronal lesions are confined to a small number of neuronal types
- most of these neurons mature late during ontogenesis
- projection neurons with a disproportionately long in relation to cell body size & sparsely myelinated axon are especially prone to the AD pathology[9]
- shrinkage of neuronal perikarya
- neuritic dystrophy
- synaptic loss (ultrastructual change)[16]
- tau oligomer-containing synapses are engulfed by microglia & astrocytes in Braak stage 3-4 Alzheimer's dementia in the absence of neurofibrillary tangle deposition[17]
- only very minor neuronal & synaptic losses observed in the prefrontal cortex of patients with Alzheimer's disease[10]*
- senescent cells identified as excitatory neurons expressing CDKN2D contain 1.8-fold larger nuclei, more lipofuscin than CDKN2D-negative neurons & overlapped with neurons containing neurofibrillary tangles[15]
* suggestion is made that synaptic dysfunction rather than synaptic or neuronal loss is implicated in Alzheimer's dementia[10]
* elevated vascular risk may influence tau burden when coupled with high beta-amyloid burden[12]
Diagnostic criteria
- Braak staging*[5]: A4 deposition and neurofibrillary tangles
- distribution of amyloid plaques varies widely
- stage A: basal neocortical areas
- stage B: superiolateral spread
- stage C: extension into primary neocortical areas
- six stages distinguished by location and severity of changes
- trans-entorhinal stages I-II: clinically silent
- involvement confined
- limbic stages III-IV: incipient AD
- involvement of CA1
- neocortical stages V-VI: fully developed AD
- involvement of all areas of association cortex
- trans-entorhinal stages I-II: clinically silent
* microglial activation & PHF-tau propagate jointly across Braak stages[14]
Notes
- neurofibrillary degeneration, progresses from the multimodal association areas to the primary sensory areas
- thus, the hierarchy of neurofibrillary degeneration follows, in an inverse manner, the hierarchy of cortical connectivity & successively higher orders of integration of information.
- disruption of the neurovascular unit may play a role in the histopathology of Alzheimer's disease.[7][8]
- blood vessels in the hippocampus may be less able to dilate than in the visual cortex, resulting in relative hypoxia during episodes of increased neuronal activity[13]
- hypoxia resulting in memory impairment as an early sign of Alzheimer's disease suggested[13]
More general terms
More specific terms
Additional terms
References
- ↑ Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11274343
- ↑ 2.0 2.1 Mirra 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 41:479-486, 1991 PMID: https://www.ncbi.nlm.nih.gov/pubmed/2011243
- ↑ 3.0 3.1 Gearing et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease. Neurology 45:461-6 1995. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/7898697
- ↑ 4.0 4.1 <Internet> http://www.alzforum.org/dis/dia/cli/Consensus.asp
- ↑ 5.0 5.1 5.2 http://www-cfas.medschl.cam.ac.uk/neuro_forms.htm
- ↑ Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82(4):239-59. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1759558
- ↑ 7.0 7.1 Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004 May;5(5):347-60. Review. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15100718
- ↑ 8.0 8.1 Bouras C, Kovari E, Herrmann FR, Rivara CB, Bailey TL, von Gunten A, Hof PR, Giannakopoulos P. Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status. J Neuropathol Exp Neurol. 2006 Mar;65(3):235-44. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16651885
- ↑ 9.0 9.1 Braak H and Tredici KD Alzheimer's pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol (2011) 121:589-595 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21516512
- ↑ 10.0 10.1 10.2 Poirel O, Mella S, Videau C et al Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer's disease at various cognitive stages. Scientific Reports, 2018; 8 (1) PMID: https://www.ncbi.nlm.nih.gov/pubmed/29343737 Free full text https://www.sciencedaily.com/releases/2018/01/180117085509.htm
- ↑ Murphy MP Amyloid-Beta Solubility in the Treatment of Alzheimer's Disease. N Engl J Med 2018; 378:391-392. Jan 25, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29365295 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1714638
- ↑ 12.0 12.1 Rabin JS, Yang HS, Schultz AP Vascular Risk and beta-Amyloid Are Synergistically Associated with Cortical Tau. Ann Neurol. 2019 Feb;85(2):272-279. Epub 2019 Jan 7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30565287
- ↑ 13.0 13.1 13.2 University of Sussex. Alzheimer's: Blood oxygen levels could explain why memory loss is an early symptom. ScienceDaily, 28 May 2021. http://www.sciencedaily.com/releases/2021/05/210528114028.htm
Shaw K, Bell L, Boyd K et al Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences. Nature Communications. 2021; May 27;12(1):3190 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34045465 Free article - ↑ 14.0 14.1 Pascoal TA, Benedet AL, Ashton NJ et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med 2021. August 21 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34446931 https://www.nature.com/articles/s41591-021-01456-w
- ↑ 15.0 15.1 Dehkordi SK, Walker J, Sah E et al. Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology. Nat Aging 2021 https://www.nature.com/articles/s43587-021-00142-3
- ↑ 16.0 16.1 Yale University New imaging scan reveals a culprit in cognitive decline of Alzheimer's. ScienceDaily. ScienceDaily, 17 February 2022 https://www.sciencedaily.com/releases/2022/02/220217090713.htm
Mecca AP, O'Dell RS, Sharp ES et al Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [ 11 C]UCB-J Alzheimers Dement. 2022 Feb 17 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35174954 - ↑ 17.0 17.1 Taddei RN, Perbet R, Mate de Gerando A et al Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease. JAMA Neurol. 2023;80(11):1209-1221. October 9, 2023. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37812432 https://jamanetwork.com/journals/jamaneurology/fullarticle/2809939
Grinberg LT. Synaptic Oligomers and Glial Cells in Alzheimer Disease. JAMA Neurol. 2023;80(11):1136-1137 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37812438 https://jamanetwork.com/journals/jamaneurology/fullarticle/2809943