Peripheral inflammation in mild cognitive impairment with possible and probable Lewy body disease and Alzheimer's disease.

ABSTRACTObjectives and design:To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups - probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer's disease (probable MCI-AD) - as well as associations with clinical features. SETTING: Memory clinics and dementia services. PARTICIPANTS: Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20). MEASUREMENTS: Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated. RESULTS: There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026). CONCLUSION: There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.

[Cholinesterase inhibitors in the treatment of dementia--are they useful in clinical practice?]. / Kolinesterasehemmere mot demens--nyttig i klinisk praksis?

BACKGROUND: Some randomized studies, mostly of short duration, have indicated that cholinesterase inhibitors (donepezil, rivastigmine and galantamine) may have a beneficial effect in Alzheimer's disease, vascular dementia and in dementia caused by Lewy body disease. The benefit of these drugs in clinical practice has not been satisfactorily documented. MATERIAL AND METHOD: Literature collected regularly for many years supplemented by extensive non-systematic searches of Pubmed and Embase. RESULTS: Only in a few placebo-controlled, double-blind, randomised studies were the patients followed for more than one year. Several clinical tests were performed, among them the Mini Mental Status (MMS)-test, which is the most commonly used test in clinical practice. The three cholinesterase inhibitors led to statistically significant results, although of limited clinical relevance, in various forms of dementia. INTERPRETATION: Based on the results obtained it could be questioned whether the observed effects are of clinical significance. Only a small proportion of patients with Alzheimer's disease seem to benefit from the cholinesterase inhibitors tested, and it is difficult to predict who will in advance. Treatment should first be evaluated after 2-4 months and subsequently on a regular basis, and accepted clinical tests should be applied.

Anti-fibrillogenic and fibril-destabilizing activity of nicotine in vitro: implications for the prevention and therapeutics of Lewy body diseases.

The aggregation of alpha-synuclein (alphaS) has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and Parkinson's disease (PD). We used fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy to examine the effects of nicotine, pyridine, and N-methylpyrrolidine on the formation of alphaS fibrils (f alphaS) from wild-type alphaS (alphaS (WT)) and A53T mutant alphaS (A53T) and on preformed f alpha Ss. Nicotine dose-dependently inhibited the f alphaS formation from both alphaS (WT) and A53T. Moreover, nicotine dose-dependently destabilized preformed f alpha Ss. These effects of nicotine were similar to those of N-methylpyrrolidine. The anti-fibrillogenic activity of nicotine may be exerted not only by the inhibition of f alphaS formation but also by the destabilization of preformed f alphaS. Additionally, this effect may be attributed to N-methylpyrrolidine moieties of nicotine.