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Frontal-executive and corticolimbic structural brain circuitry in older people with remitted depression, mild cognitive impairment, Alzheimer's dementia, and normal cognition.

ABSTRACT: A history of depression is a risk factor for dementia. Despite strong epidemiologic evidence, the pathways linking depression and dementia remain unclear. We assessed structural brain alterations in white and gray matter of frontal-executive and corticolimbic circuitries in five groups of older adults putatively at-risk for developing dementia- remitted depression (MDD), non-amnestic MCI (naMCI), MDD+naMCI, amnestic MCI (aMCI), and MDD+aMCI. We also examined two other groups: non-psychiatric ("healthy") controls (HC) and individuals with Alzheimer's dementia (AD). Magnetic resonance imaging (MRI) data were acquired on the same 3T scanner. Following quality control in these seven groups, from diffusion-weighted imaging (n = 300), we compared white matter fractional anisotropy (FA), mean diffusivity (MD), and from T1-weighted imaging (n = 333), subcortical volumes and cortical thickness in frontal-executive and corticolimbic regions of interest (ROIs). We also used exploratory graph theory analysis to compare topological properties of structural covariance networks and hub regions. We found main effects for diagnostic group in FA, MD, subcortical volume, and cortical thickness. These differences were largely due to greater deficits in the AD group and to a lesser extent aMCI compared with other groups. Graph theory analysis revealed differences in several global measures among several groups. Older individuals with remitted MDD and naMCI did not have the same white or gray matter changes in the frontal-executive and corticolimbic circuitries as those with aMCI or AD, suggesting distinct neural mechanisms in these disorders. Structural covariance global metrics suggested a potential difference in brain reserve among groups.

SUBMITTER: Rashidi-Ranjbar N

PROVIDER: S-EPMC7360554 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum. OBJECTIVE:To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes. METHODS:Patient-level longitudinal data from the National Alzheimer's Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon. RESULTS:Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy. CONCLUSION:Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.

Project description:BackgroundLeukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time.MethodsThis longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models.ResultsIn AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes.ConclusionsThe use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.

Project description:BackgroundFew studies have addressed whether anticholinergic (AC) medications for overactive bladder (OAB) cause cognitive decline in individuals with existing cognitive impairment, and whether the APOE ε4 gene increases this risk.ObjectiveTo determine whether OAB AC use is associated with a clinically relevant change in cognitive measures among adults with normal and abnormal cognition.Design setting and participantsThis was a retrospective cohort study using data from the National Alzheimer's Coordinating Center. Patients were enrolled at specialized centers in the USA between 2005 and 2019. Patients with existing OAB AC use, missing APOE ε4 status, and confounding neurologic diagnoses were excluded. New users of an OAB AC were matched 1:1 to patients not taking an OAB AC using propensity scores.InterventionNew use of oxybutynin, tolterodine, solifenacin, trospium, darifenacin, or fesoterodine.Outcome measurements and statistical analysisThe outcome was a change in cognitive function, measured as a ≥1-point increase on the Clinical Dementia Rating (CDR) instrument or a ≥3-point decrease on the Mini-Mental State Examination (MMSE). Conditional logistic regression with odds ratios (ORs) was conducted. We also tested for APOE ε4 effect modification.Results and limitationsAmong 18 835 eligible patients, 782 matched pairs were identified. The most common OAB ACs were oxybutynin (38%) and tolterodine (23%). There was no significant increase in the risk of a clinically relevant cognitive decline among OAB AC users (CDR: OR 1.38, 95% confidence interval [CI] 0.93-2.05; p = 0.11, MMSE: OR 1.06, 95% CI 0.79-1.43; p = 0.70). There was no significant interaction between APOE ε4 status and OAB AC use for the CDR (p = 0.38) or MMSE (p = 0.95) outcomes. Users of oxybutynin or tolterodine had numerically higher odds of a change on the CDR test (OR 1.65, 95% CI 0.98-2.77) that was close to statistical significance (p = 0.06). Limitations include the inability to determine medication dose or duration, and residual confounding.ConclusionsOAB AC use was not associated with a significant change in cognitive function among individuals with normal and abnormal cognition. Further research is necessary to determine if oxybutynin and tolterodine are significantly more likely to cause cognitive decline.Patient summaryUse of a specific class of overactive bladder medication was not associated with negative changes in brain function among patients with either normal or abnormal function. A genetic risk factor for Alzheimer's disease did not predispose individuals to cognitive decline when taking these drugs. Two of the drugs (oxybutynin and tolterodine) may lead to a higher risk of cognitive decline in comparison to other drugs, and this needs further research.

Project description:It is increasingly agreed upon that cognitive and audiological factors are associated with self-perceived hearing handicap in old adults. This study aimed to compare self-perceived hearing handicap among mild cognitive impairment (MCI) subgroups and a cognitively normal elderly (CNE) group and determine which factors (i.e., demographic, audiometric, or neuropsychological factors) are correlated with self-perceived hearing handicap in each group. A total of 46 MCI patients and 39 hearing threshold-matched CNE subjects participated in this study, and their age ranged from 55 to 80 years. The MCI patients were reclassified into two groups: 16 with frontal-executive dysfunction (FED) and 30 without FED. All subjects underwent audiometric, neuropsychological, and self-perceived hearing handicap assessments. The Korean version of the Hearing Handicap Inventory for the Elderly (K-HHIE) was administered to obtain the hearing handicap scores for each subject. After controlling for age, years of education, and depression levels, we found no significant differences in the K-HHIE scores between the MCI and the CNE groups. However, after we classified the MCI patients into the MCI with FED and MCI without FED groups, the MCI with FED group scored significantly higher than did both the MCI without FED and the CNE groups. In addition, after controlling for depression levels, significant partial correlations of hearing handicap scores with frontal-executive function scores and speech-in-noise perception performance were found in the MCI groups. In the CNE group, the hearing handicap scores were related to peripheral hearing sensitivity and years of education. In summary, MCI patients with FED are more likely to experience everyday hearing handicap than those without FED and cognitively normal old adults. Although educational level and peripheral hearing function are related to self-perceived hearing handicap in cognitively normal old adults, speech-in-noise perception and frontal-executive function are mainly associated with hearing handicap in patients with MCI.

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Frontal-executive and corticolimbic structural brain circuitry in older people with remitted depression, mild cognitive impairment, Alzheimer's dementia, and normal cognition.

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