Frontal Lobe Function Correlates with One-Year Incidence of Urinary Incontinence in Elderly with Alzheimer Disease

Abstract

Background: Urinary incontinence (UI) is frequently observed in patients with Alzheimer’s disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear.

Objects: To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD.

Methods: The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia behavior disturbance scale subscale, which was completed by the patients’ caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed.

Results: During 1-year follow up (mean: 377.4±83.7 days), the incidence of UI was 12.1% (n = 26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI = 9.3±2.8 versus 7.8±2.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.66–0.94) and the use of CCB (OR = 2.72, 95% CI = 1.09–6.77) were significantly associated with UI at 1 year.

Conclusion: The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD.

Keywords

Alzheimer’s disease calcium channel blocker cholinesterase inhibitors frontal lobe function urinaryincontinence

INTRODUCTION

Dementia and urinary incontinence (UI) are frequent disorders in the elderly and often coexist. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for approximately 60% of all cases [1]. AD is characterized by cognitive deficits, especially memory dysfunction, and progressive deterioration in functional performance [1]. In elderly persons with AD, UI is an embarrassing problem that leads to physical and psychological adverse outcomes, such as urinary tract infection, impaired sleep, falls, depression, and lower quality of life [2 –4]. UI is a major cause of increased caregiver’s burden and is one of the key factors in deciding to institutionalize persons with dementia previously living at home [5 –7].

The mechanism of UI in AD patients has not been fully clarified. In community-dwelling elderly, several studies showed that factors associated with UI are obesity, lower physical function, depression, and general health [8 –10]. Cognitive decline is also associated with UI in healthy elderly [11, 12]. In persons with AD, the prevalence of UI increases with disease progression. In severe-stage AD, the prevalence of UI is over 50%, and it seems likely that UI occurs secondary to severe cognitive and physical dysfunction (functional UI) [5, 13]. However, UI is found even in early-stage AD [5]. In addition to the usual risks for UI in the elderly, there could be other AD-specific predictive factors for UI, particularly in the early stage of AD. Hashimoto et al. suggested that the risk of UI is increased in AD patients treated with donepezil, a cholinesterase inhibitor [14]. In another cross-sectional study which explored key cognitive domains and behavioral problems associated with UI in AD, lower performance in verbal fluency and behavioral problems including agitation, disinhibition, and impaired attention and orientation were related to UI [13]. Lower performance in verbal fluency test and such behavioral problems may reflect impaired frontal lobe-related function. The longitudinal study focused on community-dwelling elderly women demonstrated a significant association between decline in Digit Symbol Substitution Test and disruptive UI, defined as urine leakage that interferes with the subject’s activities, although they failed to show a significant correlation between Trail Making Test and UI [12]. The Digit Symbol Substitution Test is used to evaluate psychomotor speed, attention, executive function, and visual scanning, which are considered frontal lobe-related functions. Based on these studies, frontal lobe function may be a key cognitive domain associated with UI. To our knowledge, there has been no longitudinal study that has identified a causal relationship between frontal lobe function and UI in AD patients.

The aim of the present study was to investigate the incidence of UI at 1 year in persons with AD by longitudinal analysis and identify whether frontal lobe function is predictive of UI in AD patients. Identification of the responsible factors for UI in persons with AD could provide the basis of prevention strategies for UI, which would greatly help to establish successful treatment and care of the elderly with AD.

METHODS

Sample

The subjects of this study were outpatients who attended the Memory Clinic at the National Center for Geriatrics and Gerontology (NCGG) of Japan during the period from March 2011 to December 2014. We recruited 351 subjects who were 60 years or older with a diagnosis of probable or possible AD based on the criteria of the National Institute on Aging-Alzheimer’s Association workgroups [15]. The entry criteria excluded patients with non-AD dementia such as vascular dementia, dementia with Lewy body, and normal pressure hydrocephalus. Out of 351 subjects, we excluded 54 patients who did not complete the neuropsychological tests or other assessments at baseline. Moreover, out of 297 subjects, we also excluded patients who had UI at baseline (n = 34, 11.4%) or did not complete the survey about UI at 1 year (n = 48), since the focus of this study was incidence of UI. Finally, we included 215 patients in the analysis.

Urinary incontinence

The absence or presence of UI was operationally assigned using the sub-items of the dementia behavior disturbance scale (DBD) [16]. Family or caregivers were asked whether the patient has experienced UI, and they scored the frequency as 0–4 points (0 never, 1 infrequent, 2 sometimes, 3 frequent, 4 always). Absence of UI was operationally assigned 0 or 1 points, and presence was assigned 2–4 points [17].

Frontal lobe function and neuropsychological tests

Neuropsychological assessment was performed by experienced, trained clinical staff. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB) [18]. FAB consists of six subtests (conceptualization, mental flexibility, programming, sensitivity to interference, inhibitory control, and environmental autonomy), and the score for each item ranges from 0 to 3. A higher score means better frontal lobe-related function. Mini-Mental State Examination (MMSE) was used to evaluate global cognitive function [19]. Memory performance was assessed by the logical memory I & II subset of the Wechsler Memory Scale-Revised [20]. Depressive mood and vitality were assessed using the 15-item Geriatric Depression Scale and Vitality Index, respectively[21, 22].

Sociodemographic and medical characteristics

Demographic data including age, sex, years of education, marital status (never married, married, divorced or widowed), and living situation (with spouse, family or alone) were obtained from the clinical charts. Smoking status, drinking status, and body mass index were also obtained from the clinical charts.

We assessed the existence of chronic disease (diabetes mellitus, hypertension, dyslipidemia, cardiac disease, cancer, and stroke) and number of medications. Polypharmacy was defined as using five or more medications [23]. Further, we assessed the use of medication to treat AD, hypertension, and overactive bladder: especially cholinesterase inhibitors (ChEIs), calcium channel blockers (CCBs), diuretics, alpha blockers, and anticholinergic drugs, since it is reported that these medications are associated with UI or lower urinary tract symptoms (LUTS) in subjects with and without dementia [14 , 25].

Physical performance and activities of daily living

Physical performance was measured by the Timed Up and Go test (TUG). Good reliability of TUG has been reported in persons with cognitive decline [26]. History of falls within the past 12 months was obtained by asking patients and their caregivers. Activities of daily living (ADL) were assessed using the Barthel index, with a score ranging from 0 to 100 (higher score indicating more independence inADL) [27].

Statistical analysis

The incidence of UI was calculated. In univariate analyses, differences in baseline characteristics between subjects with and without UI at 1 year were analyzed using the unpaired t-test for parametric variables, Mann-Whitney U test for nonparametric variables, and chi-squared test or Fisher’s exact test for categorical variables, as appropriate.

In multivariate analysis, we performed backward stepwise logistic regression analysis with entered demographic data including age, sex, education, marital status, and living situation and potential cofounding variables with p < 0.2 in univariate analyses. In the backward stepwise logistic regression analysis, the variables with the highest p values were eliminated one by one until all the remaining variables had p≤0.2.

Statistical analysis was carried out using STATA 13.1 (Stata Corp, College Station, Texas, USA). p values < 0.05 were considered statistically significant.

RESULTS

During the 1 year follow-up, out of 263 subjects, 48 subjects dropped out of the study (follow-up rate: 81.7%). We compared baseline characteristics between subjects who had dropped out and subjects who had not dropped out at the 1 year survey. Subjects who dropped out tended to have experienced one or more falls more than those who did not drop out (n = 21 [43.8%] versus n = 55 [25.6%], p = 0.01). We further investigated the Fall Risk Index (FRI) at the baseline [28]. The FRI is composed of 21 questions to detect the risk of falls, included the following 3 subcategories: physical function, geriatric syndrome, and environmental hazards. The subjects who dropped out had higher fall risk associated with environmental factors, but not with physical function and geriatric syndrome, than those who completed the study (data not shown). There were no differences in baseline physical, neuropsychological and medical conditions among the two groups, and an increased risk of environmental factors may contribute to the difference in history of falls at baseline.

Table 1 shows the baseline characteristics of the subjects who completed the study. The values were compared between subjects with and without UI at 1 year. At baseline, mean age of 215 subjects was 77.6±6.4 years and 149 (69.3%) were female. Mean follow-up was 377.4±83.7 days. The incidence of UI at 1 year was 12.1% (n = 26), with no gender difference; 15.2% (n = 10) in male subjects and 10.7% (n = 16) in female subjects (p = 0.36).

In univariate analyses, subjects with UI at 1 year had significantly lower performance of FAB (no UI versus UI = 9.3±2.8 versus 7.8±2.7, p = 0.01) and tended to have lower performance of logical memory I (3.6±3.2 versus 2.6±3.1, p = 0.07). ChEI users and CCB users were more likely to have UI at 1 year (ChEI: n = 137 72.5%] versus n = 24 [92.3%], p = 0.03, CCB: n = 58 [30.7%] versus n = 13 [50.0%], p = 0.05). Additionally, there was a difference in the follow up period (372±83.8 versus 412.0±75.4, p = 0.02) (Table 1).

In multivariate analysis, we performed stepwise logistic regression by entering demographic data and potential cofounding variables that were shown to associate with UI at 1 year with p < 0.2 (age, living situation, Barthel index, history of falls, Vitality Index, FAB, logical memory I & II, medication, stroke, and follow-up duration). As a result, FAB (OR = 0.79, 95% CI = 0.66–0.94) and use of CCB (OR = 2.72, 95% CI = 1.09–6.77) were significantly associated with UI at 1 year. Though it was not statistically significant, subjects who were taking ChEIs also tended to have UI at 1 year (OR = 4.48, 95% CI = 0.96–20.86) (Table 2).

DISCUSSION

The present study examined factors associated with UI at 1 year in patients with AD by longitudinal analysis. We firstly demonstrated that the incidence of UI at 1 year was 12.1% in subjects with AD, and that FAB and use of CCB were predictive factorsfor UI.

To date, several studies have reported various prevalence and incidence of UI in the elderly. Inconsistency among the studies may have resulted from different age, sex and race of the study populations, and/or diagnostic methods of UI. A quantitative meta-analysis demonstrated that the annual incidence of UI ranges from 1.6–5.8% in elderly aged 60 or older [29]. In our study participants with AD, the incidence of UI at 1 year was 12.1%, which is substantially higher than that of previous studies. We assessed the presence of UI by questionnaire, which was answered by the patients’ caregivers. Considering that caregivers may not notice the presence of UI in some cases, it seems likely that the true incidence of UI was actually higher. Our previous study found that the prevalence of UI was around 10% even in the early stage of AD [5]. Although UI is considered a major complication in the advanced stages of AD, our results strongly suggest that the prevalence of UI increases yearly by more than 10% from the early stages of AD.

As predictive factors for UI in persons with AD, FAB, but not MMSE or logical memory, was associated with incidence of UI after adjustment for potential cofounders. A previous cross-sectional study demonstrated that lower performance in verbal fluency and behavioral problems including agitation, disinhibition and impaired attention and orientation were associated with UI in the elderly with AD [13]. Lower performance in verbal fluency and these behavior problems may reflect impaired frontal lobe-related function. FAB assesses several aspects of frontal lobe function. The results of our longitudinal study agreed with previous results, and extended the notion that frontal lobe function closely associates with UI.

In this context, frontal lobe function was associated with UI independently of lower physical performance and impairment of activities of daily living. Therefore, in early-stage AD, UI should be considered as a clinical manifestation of altered frontal brain function, and not a consequence occurring secondary to deterioration of physical function and/or behavioral problems.

The mechanism underlying the association between frontal lobe dysfunction and UI is not fully understood, although a number of studies have examined brain control of bladder function using functional brain imaging methods such as single photon computerized tomography (SPECT), positron emission tomography (PET), and functional MRI (fMRI). Fowler et al. reviewed these brain imaging studies and proposed a working model of brain activity during bladder filling and emptying [30, 31]. Brain areas involved in the regulation of micturition include the thalamus, insula, prefrontal cortex, anterior cingulate, peri-aqueductal grey, pons, medulla, and supplementary motor area [31]. Tadic et al. demonstrated that connections between forebrain and brainstem structures are crucial in control of the bladder and sphincter in humans [32]. Recently, it has been reported that white matter hyperintensity and cerebrovascular disease in the medial frontal regions are associated with UI or detrusor overactivity [17 , 34]. Lee et al. showed that the most common type of UI is urgency UI, and detrusor overactivity is often found in persons with AD [35]. Based on these observation, frontal lobe function seems to have a pivotal role in bladder control, especially regulation of the micturition reflex.

It should be emphasized that frontal lobe function can be improved by cognitive training, physical exercise, and/or multi-domain intervention involving nutritional guidance, exercise, cognitive training, social activity, and intensive management of vascular risk factors in community-dwelling elderly with mild cognitive impairment [36 –38]. A controlled trial focused on patients with AD also showed that multimodal exercise intervention including motor activities and cognitive tasks improved frontal lobe function measured by FAB [39]. Further intervention study is required to clarify the effects of improvement of frontal lobe function on prevention of UI in persons with AD.

The present study showed that the use of CCB was associated with the incidence of UI at 1 year. CCBs are one of the first-line drugs to treat hypertension in elderly people. Elhebir et al. reported an association between the use of CCB and increasing severity of LUTS such as urinary frequency, urgency, and nocturia in subjects aged≥40 (mean age; 72.1±13.7) years [24]. It has been reported that other antihypertensive medications, such as angiotensin II receptor blockers and β receptor antagonists, also increased the severity of LUTS [40]. Although our study did not assess the subtypes of LUTS, our data showed a significant association between the use of CCB and the incidence of UI at 1 year. These data, together with previous literature, indicate that physicians should regularly check LUTS including UI in demented patients who are taking antihypertensive medication.

In this study, subjects who were taking ChEIs also tended to have UI at 1 year. ChEIs are the mainstay of treatment of AD, and ChEIs were taken by 74.9% of our subjects. However, it is still controversial whether the use of ChEI causes UI in AD or not. Some studies indicated that the use of ChEI did not increase the risk of UI [41, 42]. On the other hand, Hashimoto et al. suggested that ChEIs may increase the risk of UI [14]. The lack of consensus indicates the need for randomized controlled trials to clarify this association.

There are several limitations of the present study. Firstly, we assessed the presence of UI using a questionnaire of DBD subscales answered by the caregivers, which may have underestimated the incidence of UI. For the precise diagnosis of UI, a UI specific questionnaire or a 24-hour pad test is recommended. Secondly, our sample size was relatively small, which may lead to type II errors, and we might have overlooked other factors having an impact on UI. Further research with a larger sample size should be conducted in the future. Moreover, the follow-up rate was 81.7% and missing subjects may have biased the incidence of UI and factors associated with UI, although baseline physical, neuropsychological, and medical conditions were not statistically significantly different between those who dropped out and those who completed the study. Thirdly, it was not possible to distinguish subtypes of UI (urgency, stress incontinence, or mixed incontinence). Furthermore, the severity of UI was not evaluated in our study participants. Detrusor overactivity, which is more prevalent in AD, can be diagnosed by urodynamic evaluation. Finally, the duration of follow-up was relatively short (1 year).

Given these limitations, this study clarified the longitudinal association between frontal lobe dysfunction and incidence of UI, and could be the basis to establish suitable prevention strategies to ameliorate UI in patients with AD.

Footnotes

ACKNOWLEDGMENTS

The authors thank the BioBank at NCGG for quality control of the clinical data.

This work was financially supported by grants from the Research Funding of Longevity Sciences (27–21, 28–15) from the National Center for Geriatrics and Gerontology.

Authors’ disclosures available online ().

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