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Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort.

ABSTRACT: BACKGROUND:Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample. OBJECTIVE:To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes. METHODS:Within a community-based autopsy cohort (N?=?420), we ascertained use of anticholinergic medications over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDD). We used modified Poisson regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between anticholinergic exposure and dementia-associated neuropathology. Inverse probability weighting was used to account for selection into the autopsy cohort. RESULTS:Heavy anticholinergic exposure (?1,096 TSDD) was not associated with greater neuropathologic changes of Alzheimer's disease; the adjusted RRs for heavy use of anticholinergics (?1,096 TSDD) compared to no use were 1.22 (95% CI 0.81-1.88) for neuritic plaque scores and 0.89 (0.47-1.66) for extent of neurofibrillary degeneration. Moderate (91-1,095 TSDD) and heavy use of anticholinergics was associated with a significantly lower cerebral microinfarct burden compared with no use with adjusted RRs of 0.44 (0.21-0.89) and 0.24 (0.09-0.62), respectively. Anticholinergic exposure was not associated with macroscopic infarcts or atherosclerosis. CONCLUSIONS:Use of anticholinergic medications is not associated with Alzheimer's disease-related neuropathologic changes but is associated with lower cerebral microinfarct burden. Further research into biological mechanisms underlying the anticholinergic-dementia link is warranteds.

SUBMITTER: Gray SL

PROVIDER: S-EPMC6154381 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort.

Gray Shelly L SL Anderson Melissa L ML Hanlon Joseph T JT Dublin Sascha S Walker Rod L RL Hubbard Rebecca A RA Yu Onchee O Montine Thomas J TJ Crane Paul K PK Sonnen Josh A JA Keene C Dirk CD Larson Eric B EB

Journal of Alzheimer's disease : JAD 20180101 2

<h4>Background</h4>Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample.<h4>Objective</h4>To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes.<h4>Methods</h4>Within a community-based autopsy cohort (N = 420), we ascertained use of anticholinergic medications over a 10-year pe ...[more]

PMID: 30056417

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Project description:BackgroundStudies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans.ObjectivesTo evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis.MethodsAmong 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology.ResultsHigher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: -0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity.ConclusionsOur findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation.

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Project description:BackgroundYellow fever is a viral hemorrhagic fever caused by yellow fever virus, a mosquito-borne flavivirus. Despite an effective vaccine, major outbreaks continue to occur around the world. Even though it is not a proven neurotropic virus, neurological symptoms in more severe clinical forms are frequent. The understanding of this apparent paradox is still rarely addressed in literature.MethodsThe brains of thirty-eight patients with yellow fever confirmed by RT-PCR, who underwent autopsy, were analyzed morphologically to identify and characterize neuropathological changes. The data were compared with brains collected from individuals without the disease, as a control group. Both cases and controls were subdivided according to the presence or absence of co-concurrent septic shock, to exclude changes of the sepsis associated encephalopathy. To verify possible morphological differences between the yellow fever cases groups, between the control groups, and between the cases and the controls, we applied the statistical tests Fisher's exact test and chi-square, with p values < 0.05 considered statistically significant.ResultsAll cases and controls presented, at least focally, neuropathological changes, which included edema, meningeal and parenchymal inflammatory infiltrate and hemorrhages, and perivascular inflammatory infiltrate. We did not find an unequivocal aspect of encephalitis. The only parameter that, after statistical analysis, can be attributed to yellow fever was the perivascular inflammatory infiltrate.ConclusionsThe neuropathological findings are sufficient to justify the multiple clinical neurologic disturbances detected in the YF cases. Since most of the parameters evaluated did not show statistically significant difference between cases and controls, an explanation for most of the neuropathological findings may be the vascular changes, consequent to shock induced endotheliopathy, associated with stimulation of the immune system inherent to systemic infectious processes. The statistical difference obtained in yellow fever cases regarding perivascular infiltrate can be can be explained by the immune activation inherent to the condition.

Project description:ImportanceAnticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.ObjectiveTo assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.Design, setting, and participantsThis nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.ExposuresThe primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).Main outcomes and measuresOdds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.ResultsOf the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.Conclusions and relevanceExposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

Dataset Information

Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort.

Publications

Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort.

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