Clinical validity of Braak neuropathological staging in the oldest-old
Department of Geriatrics, University Hospitals of Geneva, Thônex-Genève, Switzerland.Acta Neuropathologica (Impact Factor: 10.76). 05/2000; 99(5):579-82; discussion 583-4. DOI: 10.1007/s004010051163
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.
- "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. "
Article: Brain pathologies in extreme old age[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.Neurobiology of aging 10/2015; DOI:10.1016/j.neurobiolaging.2015.10.009 · 5.01 Impact Factor
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- "In the oldest-old population, it is unclear whether Ab and tau pathologies correlate with cognitive status. There are reports of a lack of association between dementia and pathology in this population (Haroutunian et al., 2008; Savva et al., 2009) as well as studies reporting strong correlations of Ab and tau pathologies with dementia (Dolan et al., 2010; Gold et al., 2000; Nelson et al., 2007). Robinson et al. (2011), (2014) showed that dementia in subjects of the 90þ Study is strongly associated with plaque and tangle measures . "
ABSTRACT: Factors associated with maintaining good cognition into old age are unclear. Decreased brain-derived neurotrophic factor (BDNF) contributes to memory loss in Alzheimer's disease (AD), and soluble assemblies of amyloid-beta (Aβ) and tau contribute to neurodegeneration. However, it is unknown whether AD-type neuropathology, soluble Aβ and tau, or levels of BDNF and its receptor tropomyosin-related kinase B (TrkB) correlate with dementia in the oldest-old. We examined these targets in postmortem Brodmann's areas 7 and 9 (BA7 and BA9) in 4 groups of subjects >90 years old: (1) no dementia/no AD pathology, (2) no dementia/AD pathology, (3) dementia/no AD pathology, (4) dementia/AD pathology. In BA7, BDNF messenger RNA correlated with Mini-Mental State Examination scores and was decreased in demented versus nondemented subjects, regardless of pathology. Soluble Aβ42 was increased in both groups with AD pathology, demented or not, compared to no dementia/no AD pathology subjects. Groups did not differ in TrkB isoform levels or in levels of total soluble tau, individual tau isoforms, threonine-181 tau phosphorylation, or ratio of phosphorylated 3R-4R isoforms. In BA9, soluble Aβ42 correlated with Mini-Mental State Examination scores and with BDNF messenger RNA expression. Thus, soluble Aβ42 and BDNF, but not TrkB or soluble tau, correlate with dementia in the oldest-old.Neurobiology of aging 09/2015; 36(12). DOI:10.1016/j.neurobiolaging.2015.08.022 · 5.01 Impact Factor
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- "Agrin is an amyloid-associated protein able to enhance Ab fibril formation and to halt Ab degradation , suggesting that agrin might not only be a structural component of senile plaques but may also contribute to Ab fibrillation. Importantly, increased soluble agrin levels were found in the postmortem hippocampus and prefrontal cortex of patients with AD compared with that in controls , with significant hippocampal changes observed in the very early stages of AD (Braak III-IV for NFTs)  . Given the early changes found in human AD tissue and our recent proteomics data, we hypothesized that agrin is a potential early synaptic biomarker for AD. "
ABSTRACT: The need for effective treatments halting Alzheimer's disease (AD) urges the discovery of the earliest possible biomarkers. Agrin is increased in the early stages of AD and is involved in amyloid-β (Aβ) fibrillation and synaptogenesis. We investigated the potential of agrin as an early AD cerebrospinal fluid (CSF) biomarker. We analyzed the agrin CSF concentration in nondemented controls (n = 20) and those with mild (n = 20) and severe (n = 20) AD. The levels of agrin CSF were not significantly divergent among the different patient groups and did not correlate with the concentration of Aβ42, total tau, phosphorylated tau, or the Mini Mental State Examination scores. However, agrin strongly correlated with age in those with dementia. The results indicate that agrin cannot be used as an early AD CSF biomarker using the current immunoassay. However, our population was relatively young; thus, the correlation between agrin and age suggests that stronger differences in agrin concentrations might be found in older groups with more heterogeneous AD pathologic features.03/2015; 1(1):75-80. DOI:10.1016/j.dadm.2014.11.008
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