Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

Alzheimer Disease↗

PubMedDate not supplied

Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer's disease in relation to dementia severity: evidence for early neocortical degeneration.

We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo.

Aged↗

PubMedDate not supplied

Melanoma-associated adhesion molecule MUC18/MCAM (CD146) and transcriptional regulator mader in normal human CNS.

The proteins MUC18 and Mader have been identified as markers of tumor progression in melanoma cells. MUC18, also known as MCAM (melanoma cell adhesion molecule) and as CD146 (endothelial antigen), is a cell adhesion molecule belonging to the immunoglobulin superfamily. Mader is a transcriptional regulator shown to negatively regulate EGR-1. As it is known that neoplastic cells of neuroectodermal origin frequently express neuron-specific molecules, we studied whether these melanoma-associated antigens are found in normal CNS tissue. We investigated the expression of MUC18/MCAM and Mader in adult human post mortem CNS tissue by immunohistochemistry, immunoblot and two-dimensional gel electrophoresis. Our results show that Mader is preferentially expressed on neurons and glial cells and that the adhesion protein MUC18/MCAM is mainly expressed on vasculature within the CNS. These observations may have important implications for further studies investigating their possible roles in cell adhesion and proliferation control within the CNS.

Adult↗

PubMedDate not supplied

Expression of T cell receptor gamma delta antigens in human brain tissue.

The human gamma delta T cell receptor (TCR) is normally expressed on lymphoid tissue. Since expression of different molecules of the T cell system has been described for human brain cells, we examined the expression of CD4 and TCR gamma delta antigens with a panel of various anti-gamma delta TCR monoclonal antibodies (mAbs) and an anti-CD4 mAb using immunohistochemistry on different regions of frozen human postmortem tissue from five different brains. We could confirm the expression of CD4 antigens. gamma delta TCR expression on brain tissue was found in different regions of the brain by immunohistochemistry. Double staining with anti-gamma delta TCR and antineuronal enolase (NSE) mAbs showed that gamma delta TCR+ cells were not stained by anti-NSE, although they were sometimes located near neurons and showed dendritic forms; they are possibly tissue-resident gamma delta T cells, as described in the skin. Polymerase chain reaction analysis using a highly sensitive primer sequence against the constant-region delta sequence supports, combined with immunohistochemistry findings, the notion that the gamma delta TCR is expressed in human brain.

Adult↗

PubMedDate not supplied

Detection of the novel cell adhesion molecule MUC18 in human brain tissue.

The implication of cell adhesion molecules (CAMs) in the mediation of the immune response to inflammatory stimuli has been shown in different neurological syndromes. The neural cell adhesion molecule (NCAM) and the myelin associated glycoprotein (MAG) are functionally important CNS-cell adhesion molecules (CAMs) and members of the immunoglobulin gene superfamily (IgSF). Both CAMs are expressed from the time of neuronal induction and myelin formation and are likely to contribute to the generally adhesive properties of neurons and oligodendrocytes. The present study describes, by means of SDS-PAGE and immunoblotting, a novel CNS antigen which is a glycoprotein detected in post mortem frontal lobe tissue of ten subjects at an M(r) 65 and 113 kD which showed the greatest sequence homology to neuronal IgSF members like NCAM. This expected membrane CAM, with probable functions in CNS cell-cell interactions, had been detected first in primary human melanoma cells, with increasing expression as tumors progress and is expected to be a developmentally regulated CAM in neuroectodermal tissues.

Animals↗

PubMedDate not supplied

Evidence of blood-cerebrospinal fluid-barrier impairment in a subgroup of patients with dementia of the Alzheimer type and major depression: a possible indicator for immunoactivation.

Serum and cerebrospinal fluid (CSF) from 44 patients with clinical probable Alzheimer's disease (AD) (subdivided in two groups with 18 early onset, EO, and 26 late onset, LO, cases), 10 patients with vascular dementia (VD) and 24 patients with major depression (MD) were assayed for concentrations of albumin and IgG. The severity of dementia was assessed with the Mini Mental State Examination. The CSF/serum ratio for albumin and IgG as well as the IgG index were used to evaluate blood-CSF barrier function. Various patients showed signs of blood-CSF-barrier (BCB) dysfunction and only few displayed evidence of local IgG synthesis in the central nervous system (CNS) in the AD, VD and in the MD group (IgG index > 0.7). The permeability of the blood-CSF barrier was not correlated to measures of dementia severity. Our data support the hypothesis of a BCB leakage in a subgroup of all investigated patients. Furthermore, we found a small number of patients with increased intrathecal IgG synthesis. Elevated CSF immunoglobulins combined with BCB impairment might be associated or caused by a general immune activation. Our data are in agreement with the assumption that an inflammatory process may play a role in a subgroup of patients with AD but also with MD and less likely in VD. In conclusion BCB impairment and elevated IgG immunoglobulin levels are unspecific either for AD, VD or MD.

Aged↗

PubMedDate not supplied

CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease.

With the arrival of effective symptomatic treatments and the promise of drugs that may delay progression, we now need to identify Alzheimer's disease (AD) at an early stage of the disease. To diagnose AD earlier and more accurately, attention has been directed toward peripheral biochemical markers. This article reviews promising potential cerebrospinal fluid (CSF) biomarkers for AD focussing on their role in clinical diagnosis. In particular, two biochemical markers, CSF total tau (t-tau) protein and the 42 amino acid form of beta-amyloid (Abeta42), perform satisfactorily enough to achieve a role in the clinical diagnostic settings of patients with dementia together with the cumulative information from basic clinical work-up, genetic screening, and brain imaging. These CSF markers are particularly useful to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias. In order to discriminate AD from other primary dementia disorders, however, more accurate and specific markers are needed. Preliminary evidence strongly suggests that quantification of tau phosphorylated at specific sites in CSF improves early detection, differential diagnosis, and tracking of disease progression in AD.

Alzheimer Disease↗