Cholinergic enhancement of functional networks in older adults with mild cognitive impairment.

OBJECTIVE: The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group. METHODS: We conducted a 3-month, double-blind, placebo-controlled study on the effects of donepezil in 27 older adults with mild memory deficits. Participants completed a delayed recognition memory task. Functional magnetic resonance imaging (fMRI) scans were collected at baseline prior to treatment and at 3-month follow-up while subjects were on a 10mg daily dose of donepezil or placebo. RESULTS: Donepezil treatment significantly enhanced the response time for face and scene memory probes when compared to the placebo group. A group-by-visit interaction was identified for the functional network connectivity of the left fusiform face area (FFA) with the hippocampus and inferior frontal junction, such that the treatment group showed increased connectivity over time when compared to the placebo group. Additionally, the enhanced functional network connectivity of the FFA and hippocampus significantly predicted memory response time at 3-month follow-up in the treatment group. INTERPRETATION: These findings suggest that increased cholinergic transmission improves goal-directed neural processing and cognitive ability and may serve to facilitate communication across functionally-connected attention and memory networks. Longitudinal fMRI is a useful method for elucidating the neural changes associated with pharmacological modulation and is a potential tool for monitoring intervention efficacy in clinical trials.

Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings.

BACKGROUND: Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of "accelerated aging" in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation. METHODOLOGY: Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex. PRINCIPAL FINDINGS: The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of "accelerated cell aging." Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05). CONCLUSIONS: These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.