Alzheimer's disease : towards a multifaceted approach in neuropathological diagnosis

• The main aim of this study has been to investigate potential neuropathological features which may play an important role in understanding the cognitive dysfunction and in making the final diagnosis of Alzheimer's disease (AD). To establish a reliable diagnosis of AD, standardisation and uniformity of the diagnostic protocols must become mandatory. Among several currently used neuropathological criteria for AD, the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) protocol has been shown to provide the best overall correlation between cognitive decline and neuritic plaques as one of the neuropathological hallmarks of disease. Post-mortem neuropathological analyses on brains of drivers who died in traffic accidents, showed AD related changes in more than 50% of the cases, suggesting that the CERAD approach is useful for studying neuropathological changes in such populations, and that AD-related cognitive impairment seems to be an important risk factor in elderly drivers. To study the neuronal degeneration in the hippocampal formation, we applied the stereological, optical dissector, technique. We found that ageing is characterised by neuronal degeneration in CAI and subicular regions, while in AD, the dentate granular cells and subiculum are mostly affected, suggesting that the type of neuronal degeneration in AD differs from that found in normal ageing. Using standardised brain sampling, dissection, and staining procedures, we found that neurofibrillary changes in cases with the early-onset AD "Swedish" double mutation on chromosome 21 follow the same pattern of neuropathological distribution as in late-onset AD. Possession of the apoE e4 allele modified the amount of pathology, and decreased the onset, but not the duration, of the disease. Further, the specific areal and laminar distribution of the neurofibrillary changes indicate degeneration of distinct neuronal populations and projection systems. In parallel with neuronal degeneration, synaptic degeneration and loss are associated with brain dysfunction. To study synaptic function in the normal human brain we performed both quantitative and immunohistochemical analyses of the regional and cellular distribution of synaptophysin, rab3a, synaptotagmin, growth associated protein GAP-43 and neurogranin. Synaptic protein density significantly varied between different cortical and subcortical regions, and specific patterns of laminar staining in the cortex and hippocampus was found for the different proteins, supporting the hypothesis that different molecular mechanisms for both synaptic plasticity and neurotransmitter release might operate in distinct neuronal circuits. In AD, synaptic loss and regenerative processes were studied using the synaptic proteins rab3a and GAP-43 as markers. Synaptic density was decreased in the frontal cortex and the hippocampus in AD, and correlated with the clinical status, but not with neurofibrillary tangles or senile plaques, supporting that synaptic pathology is an important event in AD, which might be independent of other types of pathology. Although a general decrease was found also for GAP-43, specific subfields of the hippocampus showed an increased GAP-43 staining, suggesting that aberrant sprouting and regenerative phenomena in AD brain shows a regional and cellular specificity, and do not always occur in parallel to synaptic degeneration. In conclusion, the selection of appropriate markers, brain tissue sampling and methodology could increase the diagnostic accuracy. To define the morphological substrate of cognitive impairment in AD we consider that it is imperative to establish a multifaceted approach for analysis of neuronal and synaptic degeneration, and neurofibrillary changes.

Nyckelord

Alzheimer's disease, CERAD, neurofibrillary tangles. neuritic plaques,apoE. synaptic proteins, rab3a, synaptophysin, synaptotagmin, GAP-43, neurogranin,neuronal degeneration, optical disector 1998

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vet (ämneskategori)

dok (ämneskategori)