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Pathological Substrates of Cognitive Decline in Alzheimer’s DiseaseGiannakopoulos P.a,c · Gold G.b · von Gunten A.c · Hof P.R.d,e · Bouras C.a,d
Departments of aPsychiatry and bGeriatrics, University of Geneva School of Medicine, Chêne-Bourg, Geneva, cDivision of Old Age Psychiatry, University of Lausanne School of Medicine, Lausanne, Switzerland; Departmentsof dNeuroscience and eGeriatrics and Adult Development, Mount Sinai School of Medicine, New York, N.Y., USA
The progressive development of Alzheimer’s disease (AD)-related lesions such as neurofibrillary tangles,amyloid deposits and synaptic loss within the cerebral cortex is a main event of brain aging.Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia dependsmore on the severity and topography of pathologic changes than on the presence of a qualitativemarker. However, several methodological problems such as selection biases, case-control design,density-based measures, and masking effects of concomitant pathologies should be taken intoaccount when interpreting these data. In last years, the use of stereologic counting permitted todefine reliably the cognitive impact of AD lesions in the human brain. Unlike fibrillar amyloid depositsthat are poorly or not related to the dementia severity, the use of this method documented thattotal neurofibrillary tangles and neuron numbers in the CA1 field are the best correlates of cognitivedeterioration in brain aging. Loss of dendritic spines in neocortical but not hippocampal areas has amodest but independent contribution to dementia. In contrast, the importance of early dendriticand axonal tau-related pathologic changes such as neuropil threads remains doubtful. Despite theseprogresses, neuronal pathology and synaptic loss in cases with pure AD pathology cannot explainmore than 50% of clinical severity. The present review discusses the complex structure/function relationshipsin brain aging and AD within the theoretical framework of the functional neuropathologyof brain aging.
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