Background Hypertension (HTN) is a risk factor for dementia and animal studies suggest that centrally active (cross the blood brain barrier) angiotensin converting enzyme (ACE) inhibitors may protect against dementia beyond HTN control. Methods Participants in the Cardiovascular Health Study cognition substudy (mean age 75 yrs) with treated HTN and no diagnosis of heart failure (n= 1054) were followed for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared to other antihypertensive agents, was associated with lower risk of incident dementia, cognitive decline (by the modified mini mental state exam, 3MSE), or incident disability in instrumental activities of daily living (IADL). Results Among 414 participants exposed to ACE inhibitors and 640 not, there were 158 cases of incident dementia. Compared to other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (HR 1.01, 95% CI 0.88–1.15), difference in 3MSE scores (−0.32 points/yr, p=0.15), or odds of IADL disability (OR (95% CI) 1.06 (0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (p= 0.01) and non-centrally active ACE inhibitors were associated with greater risk of incident dementia (adjusted HR 1.20 (1.00–1.43) per year of exposure) and greater odds of IADL disability (adjusted OR 1.16 (1.03–1.30) per year of exposure) compared to other anti-HTN drugs. Conclusions While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within class differences in regards to these outcomes. These results should be confirmed with an RCT of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide (mAEA), the hydrolysis resistant analogue of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain, and provide a potential new target for the treatment of nicotine addiction.

Objectives:Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).Methods: Participants included 99 women without dementia aged 70-79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.Results: Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1-C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2-85.1) and 7.6-fold increased risk of AD (95% CI 0.9-62.1), respectively. The highest tertiles of ceramide d18:1-C24:0 (hazard ratio [HR] ϭ 5.1, 95% CI 1.1-23.6) and lactosylceramide (HR ϭ 9.8, 95% CI 1.2-80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD. Conclusions:Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies. Neurology ® 2012;79:633-641 GLOSSARY A␤ ϭ amyloid-␤; AD ϭ Alzheimer disease; amu ϭ atomic mass units; APP ϭ amyloid precursor protein; BACE-1 ϭ ␤-site APP cleaving enzyme 1; BMI ϭ body mass index; CI ϭ confidence interval; DSM-IV ϭ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ESI-MS/MS ϭ electrospray ionization tandem mass spectrometry; HDL ϭ high-density lipoprotein; HR ϭ hazard ratio; MCI ϭ mild cognitive impairment; MMSE ϭ Mini-Mental State Examination; SM ϭ sphingomyelin; WHAS II ϭ Women's Health and Aging Study II.Lipidomic, metabolomic, and targeted approaches have identified pathways and products of sphingolipid metabolism that are altered early in the course of Alzheimer disease (AD). [1][2][3][4][5] Ceramides facilitate the regulation of ␤-site APP cleaving enzyme 1 (BACE-1) and ␥-secretase activity and amyloid precursor protein (APP) processing and trafficking. Evidence also suggests that glycosphingolipids bind amyloid-␤ (A␤) at the cell surface and form domains that facilitate the oligomerization and fibril formation of A␤. 6 -10 In addition to these roles, ceramide is aFrom the Division

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

Objectives: The aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or b-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI).Methods: Secondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n 5 1,928) or MCI (n 5 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders.Results: Diuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31-0.82), 0.31 in ARB (95% CI 0.14-0.68), 0.50 in ACE-I (95% CI 0.29-0.83), 0.62 in CCB (95% CI 0.35-1.09), and 0.58 in BB (95% CI 0.36-0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio 5 0.38, 95% CI 0.20-0.73).Conclusions: Diuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI. Observational studies suggest protective effects of antihypertensive medications on risk of dementia 1-6 independently or in addition to their ability to control blood pressure, and that these effects may be specific to the class of drugs to which they belong. A postmortem study of subjects with Alzheimer disease (AD) dementia showed that treated hypertensive subjects had less AD dementia neuropathology than untreated hypertensive and normotensive subjects, 7 while imaging studies showed preserved hippocampus in normotensive and treated hypertensive subjects. 8,9 However, clinical trials evaluating antihypertensive medications for dementia prevention found no risk reduction, 10-12 which could be explained by dementia being a secondary outcome and therefore insufficiently powered. Additionally, the majority of these studies were confounded by combined antihypertensive medication use 11,13-16 to achieve acceptable blood pressure. There are few studies with equivocal evidence regarding the role of hypertension (HTN) and no randomized clinical trials evaluating the effects of antihypertensive medications on progression of mild cognitive impairment (MCI) to dementia.

Background-CB 1 cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors, however, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys.

Anandamide is an endogenous ligand for brain cannabinoid CB 1 receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of ␦-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3Ј-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB 1 receptor antagonist rimonabant, but not the vanilloid VR 1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl) 8,11, and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.The endogenous cannabinoid (CB) system, which is targeted by the psychoactive ingredient in cannabis, ␦-9-tetrahydrocannabinol (THC), comprises receptors termed CB 1 and CB 2 (and others not yet identified) endogenous compounds that activate these receptors and enzymes involved in the synthesis and degradation of these endogenous cannabinoids

Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB 1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of ⌬ 9 -tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB 1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB 1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3Ј-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.Nicotine, the main psychoactive component of tobacco, plays a major role in tobacco dependence by acting directly as a reinforcer of drug-seeking and drug-taking behavior (Le Foll and Goldberg, 2006). In rats, nicotine can reinforce drug self-administration behavior (Corrigall and Coen, 1989) and induce conditioned place preference (CPP) (Le Foll and Goldberg, 2005), and it can trigger relapse to previously acquired drug-seeking behavior (Shaham et al., 1997). Nicotine's rewarding effects are believed to stem from its ability to activate the mesolimbic dopaminergic system by enhancing firing rate and burst firing of dopaminergic neurons in the ventral tegmental area (VTA) (Mereu et al., 1987) and increasing dopamine release in terminal areas, especially in the nucleus accumbens shell (Pontieri et al., 1996).Recent findings suggest that behavioral and motivational