engleski

Pathological substrates of Alzheimer's disease: review and need to update criteria with CSF biomarkers

The first NIA (National Institute on Aging) neuropathological diagnostic criteria for AD, were based on quantification of minimal SP (senile plaques) cortical densities as a function of age (Khachaturian Z.S., Arch. Neurol. 1985). They were not broadly accepted because SP formation may be partly a benign age-related phenomenon (making criteria less sensitive), the cortical region for quantification as well as the role of the clinical history were not well defined (making criteria less specific and non-comparable) and NFT (neurofibrillary tangles) were not considered. Therefore, another set of standardized criteria known as CERAD (Consortium to Establish a Registry for Alzheimer's disease) was proposed (Mirra S.S. et al., Neurology 1991). These semiquantitative criteria were determined as a function of the development of neocortical NP (neuritic plaques) in the superior temporal gyrus, prefrontal cortex and lower parietal lobule using modified Bielschowsky or thioflavin S staining in three age groups (less than 50, 50 to 75, and over 75 years). Based on the combination of clinical information and NP score, three levels of diagnostic certainty were assessed (definite, probable, or possible AD). Besides the fact that the hippocampal formation was again absent from criteria (despite its characteristic and crucial involvement in the initial stages of typical AD), the major weakness of CERAD criteria was that they relied only upon the amyloid cascade hypothesis and did not consider neocortical NFT, although these are not present in normal aging (except in entorhinal cortex) and correlate strongly with dementia severity (Bierer L. et al., Arch. Neurol. 1995). In an attempt to reconciliate the amyloid cascade hypothesis with the major role of NFT in clinicopathological correlations, in 1997, the more rigorous NIA-RI (Reagan Institute) consensus recommendations for the postmortem diagnosis of AD were issued. These procedures use CERAD protocols for tissue processing, as well as semiquantitative assessment of AD lesions that must be made in several neocortical areas, hippocampus, substantia nigra and locus coeruleus and they also take into account the Braak staging system. In contrast to CERAD criteria which incorporate clinical data to provide a neuropathological diagnosis, NIA-RI criteria primarily aim to define the likelihood that clinical dementia was really due to AD lesions. Because NIA-RI criteria take into account the number of neocortical NFT, in comparison to CERAD they are more specific but less sensitive, as there is a considerable number of demented patients with AD who have low numbers of neocortical NFT. It can be concluded that we still do not have definitive neuropathological criteria. On the other hand, a crucial problem of premortal diagnosis is that the reliability of both clinical and neuroimaging methods is a function of disease severity, and therefore, there is a risk of increasing overlap with non-AD pathology, psychiatric illness and healthy aging (ICD-10, DSM-IV-TR, NINCDS-ADRDA), particularly in presence of comorbidities and cases of atypical AD syndromes, such as anterior (frontotemporal) and posterior (parietotemporo-occipital) variants of AD, focal, lobar or gyral progressive degenerative syndromes (van Gunten A. et al., Brain Res. Rev. 2006). Moreover, the clinical spectrum of symptoms of these conditions more closely correspond to the functional anatomy of the affected brain areas than to the underlying pathology. However, in the last several years it has been clearly established that cerebrospinal fluid (CSF) biomarkers, particularly phospho-tau proteins, demonstrate a considerable increase in predictive value over existing algorithms comprising clinical, neurophychological and imaging modalities (Hampel H. et al., Arch. Gen. Psychiatry 2004, de Leon M.J. et al., J. Int. Med. 2004, Hansson O. et al., Lancet Neurol. 2006). Consequently, the time has come to include CSF examination as a part of routine diagnostic workup for suspected AD in both clinical and neuropathological evaluation of a patient.

Alzheimer's disease ; neuropathology ; diagnosis ; criteria ; biomarkers ; cerebrospinal fluid ; phospho-tau proteins

nije evidentirano