Exploratory study on immune phenotypes in Alzheimer's disease and vascular dementia.

BACKGROUND AND PURPOSE: The differentiation of Alzheimer's disease (AD) dementia from vascular dementia (VaD) and mixed-type dementia (mixed dementia) requires stepwise analysis and usually occurs late in the disease process. Early diagnosis and therapy monitoring would benefit greatly from the identification of biomarkers of neurodegeneration, especially blood biomarkers. To this end, the aim of the present pilot study was to investigate differences in the distribution of peripheral T-cell populations in patients with AD compared to VaD and mixed dementia. METHODS: Flow cytometry was performed on blood samples from 11 patients with AD, six with VaD and six with mixed dementia, as well as 17 healthy control subjects (HCs). CD4+ and CD8+ T cells were typed for expression of CD45, CD27, CD28, CD25, FoxP3, CCR4 and CCR6; the other leukocytes were also assessed. Functionally, immune cell uptake of the ß-amyloid (Aß) toxic fragment (Aß1-42 ) was also evaluated. RESULTS: A higher proportion of CD4+CD28- memory T cells and a reciprocal reduction of CD4+CD28+CD27+ naïve T lymphocytes was detected in all patient groups relative to controls. Significantly fewer CD4+CD25+FoxP3 regulatory T cells were present in patients with VaD, and significantly more CCR6+ and CCR4+ CD4+ T cells in those with AD. Higher CCR6+ T-cell frequencies were also present in patients with mixed dementia, potentially due to the inflammation and immune cell chemoattraction triggered by Aß. CONCLUSIONS: The present study was a comprehensive investigation comparing different kinds of dementia, revealing differentially expressed peripheral markers that are potentially useful for early AD, VaD and mixed dementia diagnoses, and that would assist in proper treatments for these disparate diseases. Validation is now required.

Assessment of health status by molecular measures in adults ranging from middle-aged to old: Ready for clinical use?

In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.

Unexpected and unexplained increase in death due to neurological disorders in 2012 in England and Wales: is cytomegalovirus implicated?

In early 2012 deaths (all-cause mortality) in England and Wales showed an unexpected and unexplained increase which continued for 18 months before abating. The highest percentage increase in deaths was noted to be for neurological degenerations (mainly dementia, Alzheimer's, Parkinson's). This study seeks to understand why increased deaths should focus on these conditions and if an unrecognized infectious outbreak could be implicated. Cause of death statistics for England and Wales were compared for 2012 versus 2011 as was the diagnosis for first outpatient appointment and inpatient admissions for these conditions. Deaths for dementia, Alzheimer's and Parkinson's showed a 15% increase with associated age specificity. The increase could not be explained by changes in the coding relating to cause of death. The increase coincided with increased GP referral (as first outpatient attendance) and inpatient admission for a range of neurological conditions. These increases were also observed on previous occasions of a similar event where deaths peaked in 2003 and 2008. A cascade of debility leading to immobility and institutionalization along with specific immune impairments appears to render those suffering from neurological degenerations sensitive to infectious outbreaks and more specifically to the particular agent behind these events. These and other studies point to outbreaks of a previously uncharacterized agent with the outbreak peaking in 2003, 2008 and 2012 (and in other years prior to these dates). Cytomegalovirus is a potential candidate and the necessary research to test this hypothesis is outlined.