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.
"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. "
[Show abstract][Hide abstract] 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.
"After mounting in Permount, the sections were studied in a photomicroscope (Zeiss Axiolab). Neuropathological alterations were estimated and rated according to Braak and Braak staging   and CERAD neuritic plaque score  . The consensus recommendations concerning the neuropathological diagnosis of AD introduced by the National Institute on Aging and the Reagan Institute  were also respected. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-β, AβPP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components.
"These results promote the notion of an overlap in AD neuropathological lesions in older subjects with or without dementia. Neuropathological studies have also shown that the association between clinical AD diagnosis and neuropathological features was more important in younger persons than in older subjects (Gold et al., 2000; Middleton et al., 2011; Savva et al., 2009). However, a possible limitation to our findings is the use of patients with non-AD cognitive disorders as controls instead of cognitively normal individuals. "
[Show abstract][Hide abstract] ABSTRACT: Increasing age is the most important risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the relationships between age and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ 1-42), total Tau and phosphorylated Tau (pTau-181), in AD and non-AD patients explored for cognitive disorders. 966 patients (AD, n=528; non-AD, n=438) were included between January 2008 and December 2010 (mean age, 69.5years; mean MMSE, 20.2) from three French memory centers. Multivariable linear regression models were used to study the relationship between CSF biomarker levels and age in AD and non-AD patients. The capacity of each CSF biomarker in discriminating patients was evaluated using the area under the receiver-operating characteristic (ROC) curves by quartile of distribution of age. In AD patients, older age was associated with higher CSF Aβ 1-42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF Aβ 1-42, higher Tau, and higher pTau-181 levels. In sex-stratified analysis, these relationships were significant only in women. Using ROC curve analysis, CSF AD biomarkers were more discriminant in younger patients than in older ones. In this clinically-based study, younger patients with AD had exacerbated CSF anomalies compared to older patients with AD. CSF biomarkers were more discriminant in younger patients than in older ones for the diagnosis of AD, especially in women. These results support the idea of an overlap in AD neuropathological lesions in oldest subjects with or without AD.
Neurobiology of Disease 02/2013; 54. DOI:10.1016/j.nbd.2013.01.023 · 5.08 Impact Factor
Camilla N Clark, Jennifer M Nicholas, Elizabeth Gordon, Hannah L Golden, Miriam H Cohen, Felix J Woodward, Kirsty Macpherson, Catherine F Slattery, Catherine J Mummery, Jonathan M Schott, Jonathan D Rohrer, Jason D Warren
Sandra E Leh, Andrea M Kälin, Clemens Schroeder, Min T M Park, Mallar M Chakravarty, Patrick Freund, Anton F Gietl, Florian Riese, Spyros Kollias, Christoph Hock, Lars Michels
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