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

University of Kuopio, Kuopio, Northern Savo, Finland
Acta Neuropathologica (Impact Factor: 10.76). 11/2006; 112(4):389-404. DOI: 10.1007/s00401-006-0127-z
Source: PubMed


Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 mum) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5-15 mum) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.

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Available from: Thomas Arzberger
    • "AD Braak stages indicate the stage of neurofibrillary tangles (Roman numerals) and senile plaques (letters) according to Braak and Braak474849. PD Braak stage refers to the stage of -synuclein (Lewy Bodies) according to Braak[50] "
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    ABSTRACT: Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states.
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    • "Seeding mechanisms as well as transsynaptic propagation processes are involved in the propagation of Ab and t (Clavaguera et al., 2009; Kane et al., 2000; Meyer-Luehmann et al., 2006; Iba et al., 2015; Peeraer et al., 2015; Stancu et al., 2015) whereas post-translational modification of proteins is required for the maturation of Ab aggregates (Thal, Walter, Saido, & Fandrich, 2015). The conversion from p-preAD to the symptomatic phase of AD, thereby, is accompanied with further propagation and maturation (Braak and Braak, 1991; Braak et al., 2006; Rijal Upadhaya et al., 2014; Thal et al., 2002). Accordingly, stopping propagation or maturation of AD pathology appears to represent interesting targets for therapeutic intervention that may already be effective in p-preAD cases. "
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    • "Quantitation of Ab-positive mature and diffuse plaques was performed based on Consortium to Establish a Registry for AD recommendations (Mirra et al., 1991). Alzheimer-type neurofibrillary tangle pathology was assessed using Braak and Braak staging (Braak et al., 2006). The extent and severity of CAA was determined based on a 4-tier grading system (Lashley et al., 2008; Olichney et al., 1996), described in Supplementary Information. "
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    ABSTRACT: Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.
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