Clinical validity of Braak neuropathological staging in the oldest-old

ArticleinActa Neuropathologica 99(5):579-82; discussion 583-4 · May 2000with2 Reads
DOI: 10.1007/s004010051163 · Source: PubMed
Several studies have demonstrated a good correlation between clinical severity and Braak's neuropathological staging in Alzheimer's disease (AD). However, nonagenarians and centenarians display a different pattern of cortical vulnerability to the neurodegenerative process compared to younger elderly, and it is not known whether correlations between clinical severity and neuropathological stages remain valid in this age group. To address this issue we compared Clinical Dementia Rating scale (CDR) scores and Braak stages in 116 patients over 90 years of age with either no cognitive impairment or very mild to severe AD. There is a strong positive correlation between CDR scores and Braak staging (Spearman coefficient = 0.66; P < 0.01). However, neuropathological staging does not distinguish cases with normal cognition (CDR 0) from those with mild cognitive changes (CDR 0.5). Unlike younger cohorts, Braak stages I and II are frequently associated with questionable dementia in this age group. Braak stage III overlaps with all CDR levels and correlates poorly with cognitive function. Braak stages IV or greater are consistently associated with at least mild dementia. Consistent with our previous neuropathological analyses of nonagenarians and centenarians, the present data suggest that the substantial involvement of the hippocampus which characterizes Braak stage IV is a key step in the development of overt clinical signs of dementia in the oldest-old. Moreover, they indicate that Braak staging represents a broad concept of the evolution of neurofibrillary tangles rather than a precise hierarchical model associated with a stepwise deterioration of cognitive abilities near the upper limit of life.
    • "Whether these individuals represent preclinical MCI remains an intriguing area of research. While several groups have investigated the neuropathology of MCI and possible/probable AD, very few have concentrated on the relationship of Braak staging to clinical dysfunction in people with NCI [41]. An investigation of a small number of NCI subjects from the Rush Religious Orders Study (RROS) cohort revealed relatively similar percentages of low (40%) and high (60%) Braak scores compared to NCI, MCI and AD subjects examined [42] demonstrated a minor association between episodic memory and neuropathology using NIA-Reagan Institute neuropathological criteria for AD, which combines the assessment of neuritic plaques using CERAD scores and NFT pathology using Braak scores [43]. "
    [Show abstract] [Hide abstract] ABSTRACT: Although the two pathological hallmarks of Alzheimer’s disease (AD), senile plaques composed of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that Aβ plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state), and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than Aβ plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including Aβ and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuron plasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.
    Full-text · Article · May 2016
    • "prodromal AD (Mufson et al., 2012a; Perez et al., 2015; Price et al., 2009; Schneider et al., 2009a) and AD (Bennett et al., 2002; Mufson et al., 1999) without concomitant dementia. Numerous studies have investigated the neuropathology of probable AD and mild cognitive impairment (MCI) in various clinical cohorts, but very few have concentrated on the relationship of Braak staging to clinical dysfunction in people with NCI (Gold et al., 2000; Price et al., 2009). An investigation of a small number of cognitively nonimpaired people from the RROS cohort revealed similar percentages of low (40%) and high (60%) Braak. "
    [Show abstract] [Hide abstract] ABSTRACT: Clinico-pathological studies reveal that some elderly people with no cognitive impairment have high burdens of neurofibrillary tangles (NFTs), a pathology associated with Alzheimer's disease. We examined a total of 123 elderly participants without dementia and free of other neurological disorders or pathologies who at autopsy were classified as Braak NFT stages of I–V. We found that women were significantly more likely to have a high Braak score. Significant associations were found between high Braak scores and entorhinal cortex amyloid load, combined hippocampal and entorhinal cortex amyloid loads with perceptual speed in the low Braak group after adjusting for age, gender and apolipoprotein E ε4 status. Elderly with preserved cognitive function show a wide range of Braak scores and plaque pathology similar to that seen in prodromal and frank Alzheimer's disease at death. These data suggest that some older people with extensive NFT and plaque pathology demonstrate brain resilience or reserve leading to preserved cognitive function.
    Full-text · Article · Oct 2015 · Neurobiology of aging
    • "In addition to prior case series, there have been excellent reviews of the findings (Hof, et al., 1996, Imhof, et al., 2007, von Gunten, et al., 2010). Both practical and theoretical challenges have been identified in terms of accurate clinical-pathological correlation in centenarians (Ding, et al., 2006a, Ding, et al., 2006b, Garcia-Sierra, et al., 2000, Gold, et al., 2000, Jellinger and Attems, 2010b, Nelson, et al., 2011b, Poon, et al., 2007, Silver, et al., 2002, Wang, et al., 1999), and most of the autopsy series that focused on centenarians have been relatively small. "
    [Show abstract] [Hide abstract] ABSTRACT: With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum.
    Article · Oct 2015
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