Neurourology and Urodynamics 24:273^275 (2005)

Preliminary Communication: Urodynamic Assessment ofDonepezil Hydrochloride in PatientsWith Alzheimer’s Disease

Ryuji Sakakibara,1* Tomoyuki Uchiyama,1 Mitsuharu Yoshiyama,1

Tomoyuki Yamanishi,2 and Takamichi Hattori11Department of Neurology, Chiba University, Chiba, Japan

2Department of Urology, Dokkyo Medical College, Tochigi, Japan

Background and Aims: Donepezil hydrochloride, a central cholinergic drug, is widely used forimproving cognitive decline in Alzheimer’s disease (AD). We investigated whether donepezil mighta¡ect the lower urinary tract (LUT) function in AD. Methods: Alzheimer’s Disease AssessmentScale cognitive subscale (ADAS-cog) (0^70, increase as impairment), urinary questionnaire, andelectromyography (EMG)-cystometry were performed in eight patients with AD before and aftertreatment with 5 mg/day of donepezil. Results: The ¢rst assessment (before donepezil) showedmoderate cognitive decline in the patients as a mean ADAS-cog score of 27.0 (range: 17^35) (normal<15). Seven patients had urinary symptoms including urinary urgency incontinence in ¢ve.EMG-cystometry revealed neurogenic detrusor overactivity in seven with a mean detrusor pressureof 44.9 cmH2O (20^101), mean bladder capacity of 202 ml (20^ 412), and post-void residuals in none.The second assessment (3 months after donepezil) showed a decrease in the ADAS-cog score to23.3 (11^35) though without statistical signi¢cance. Urinary incontinence disappeared in one andnone had a new onset of incontinence. EMG-cystometry revealed an increase in the detrusor pres-sure on overactivity to 54.1 cmH2O (20^122), but also an increase in the bladder capacity to 234 ml(80^400), and post-void residuals in one (40 ml). Conclusion: Although the number of our patientswas small, it seems possibly that donepezil could ameliorate cognitive function without seriousadverse e¡ects on the LUT function in patients with AD. Neurourol. Urodynam. 24:273 ^275, 2005.� 2004 Wiley-Liss, Inc.

Key words: Alzheimer’s disease; cholinergic; detrusor overactivity; donepezil hydrochloride;urinary incontinence

INTRODUCTION

Donepezil hydrochloride is a selective central acetylcholi-nesterase (AchE) inhibitor, which decreases degradation ofacetylcholine in the brain, then increasing the concentrationof acetylcholine in the synaptic cleft [Shinotoh et al., 2001].This drug is widely used to ameliorate cognitive decline inpatients with Alzheimer’s disease (AD) [Rogers et al., 1998;Burns et al., 1999] which is thought to be due to a decrease incholinergic innervation of the cerebral cortex and the basalforebrain [Becker, 1991]. Since the bladder is innervated bythe parasympathetic cholinergic nerves [de Groat et al., 1995]and neurogenic lower urinary tract (LUT) dysfunction occursin a subset of patients with AD [Resnick et al., 1989; Sugiyamaet al., 1994] there has been a controversy that the central AchEinhibitors might exacerbate urinary incontinence in thosepatients [Hashimoto et al., 2000]. However, no urodynamicdata is available to our knowledge. The purpose of this studyis to investigate whether donepezil treatment may a¡ect theLUT function in patients with AD.

MATERIALS AND METHODS

We recruited eight patients with AD who met the clinicaldiagnostic criteria [American Psychiatric Association, 1994].

All patients were ambulatory without an aid. Brain magneticresonance imaging (MRI) scan showed minimal to moderateatrophy of the hippocampus and the adjacent mesial temporalcortex in all patients. In addition, six of the patients also hadmild leukoaraiosis as grade 1 in ¢ve and grade 2 in one on a 0^4 scale of Brant-Zawadzki et al. [1985] and Sakakibara et al.[1999]. There were ¢ve men and three women, mean age77 years (range: 69^94), mean duration of disease 2.3 years(1^5). None of the patients were taking drugs that might a¡ecteither cognitive or lower urinary tract function. Cognitivefunction was assessed by Alzheimer’s Disease AssessmentScale; cognitive subscale (ADAS-cog) [Rosen et al., 1984]which scores range from 0 to 70 with decreasing scores indi-cating improvement. A questionnaire of LUT symptomsincluded storage (urgency, frequency, and incontinence) andvoiding symptoms (voiding di⁄culty) [Sakakibara et al.,2001] which were ¢lled in by the patients and their caregivers.

*Correspondence to: Ryuji Sakakibara, Department of Neurology, ChibaUniversity, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.E-mail: sakakibara@faculty.chiba-u.jpReceived 31 July 2002; Accepted 19 November 2004Published online 16 December 2004 inWiley InterScience(www.interscience.wiley.com)DOI 10.1002/nau.20102

�2004Wiley-Liss, Inc.

Urodynamic studies were performed with informed consentfrom the patients and their families. Normal volume of post-void residuals is under 30 ml, which was measured by an 8Ftransurethral catheter.We performed medium-¢ll (50 ml/minsaline at room temperature) urodynamic study on all patientswith a urodynamic computer (Lifetech, Inc., Houston, TX;Janus) and an electromyographic computer (Nihon Kohden,Inc.,Tokyo, Japan; Neuropack S), simultaneously monitoringand recording the detrusor pressure (Pdet), which is a di¡er-ence of intra-vesical pressure (via a double-lumen 8F tranure-thral catheter) and intra-abdominal pressure (via a 10F rectalcatheter with a small balloon at the tip ¢lled with minimumamount of saline), external sphincter EMG activity (via a con-centric needle electrode placed in the external anal sphincter),and urinary £ow (via a uro£owmeter). Normal values for ¢rstsensation and bladder capacity are 100^300 ml and 200^600 ml, respectively. Detrusor overactivity is de¢ned as a pha-sic contractionwith the detrusor pressure rise over10 cmH2O.Uninhibited sphincter relaxation is de¢ned as an involuntaryrelaxation of the sphincter during bladder ¢lling. Detrusor-sphincter dyssynergia is de¢ned when the patient is unableto relax the sphincter on voiding detrusor contraction. Themethods and de¢nitions used for the urodynamic studies con-formed to the standards proposed by the International Conti-nence Society [Abrams et al., 2002].We then started donepezilwith a recommended dose of 3 mg once a day, in order to avoidpossible initial adverse e¡ects such as nausea or appetite loss.Two weeks later, we updosed donepezil to a regular dose of5 mg once a day. After 3 months, we repeated the cognitivetest, urinary questionnaire, and urodynamic studies. Statisti-cal analysis was performed by Student’s paired t-test.

RESULTS

The First Assessment (Before Donepezil)

On the ¢rst assessment, all patients had moderate cognitivedecline, presenting as a mean ADAS-cog score of 27 (range:17^35) (normal <15) (Fig. 1). Seven patients were revealed tohave LUT symptoms. Urinary incontinence was the mostcommon (¢ve patients; at least once a week in two and at leastonce a month in three). Four patients had urgency inconti-nence, but one patient had functional incontinence. The nextcommon were nighttime frequency (more than twice) anddaytime frequency (more than eight times) (four patients), fol-lowed by voiding di⁄culty (two patients). EMG-cystometryrevealed neurogenic detrusor overactivity in seven with amean overactive pressure of 44.9 cmH2O (20^101 cmH2O)(Fig. 2), mean bladder capacity of 202 ml (20^412 ml) (Fig. 3),and uninhibited sphincter relaxation in one. None of the pati-ents had detrusor-sphincter dyssynergia or post-void residuals.

The Second Assessment (3 Months After Donepezil)

All patients were well tolerated with the donepeziltreatment. One patient initially had mild abdominal discom-

fort, which soon disappeared without medication. As com-pared with the ¢rst assessment, cognitive function of thepatients tended to ameliorate as shown by a decrease of meanADAS-cog score to 24.5 (11^35) (Fig. 1), although there was nostatistical signi¢cance. LUTsymptoms were still found in theseven patients. However, urinary incontinence disappeared inone and persisted in four (at least once a week in one and atleast once a month in three, all urgency type). None had a

Fig. 1. Scores of Alzheimer’s Disease Assessment Scale cognitive

subscale (ADAS-cog). Pre: Before donepezil treatment; post, after

donepezil treatment. The score ranges from 0 to 70 with decreasing

scores indicating improvement. Horizontal bars indicate average

values.

Fig. 2. Detrusor pressure on detrusor overactivity (seven patients).

Pre: Before donepezil treatment; post, after donepezil treatment.

Horizontal bars indicate average values.

274 Sakakibara et al.

new onset of incontinence. Other symptoms included night-time frequency in four, daytime frequency in three, and void-ing di⁄culty in two. Despite the modest improvement of theurinary symptoms, detrusor overactivity persisted in sevenwith an increase in mean overactive pressure to 54 cmH2O(20^122 cmH2O) (Fig. 2), without statistical signi¢cance.However, mean bladder capacity rather increased to 234 ml(80^400 ml) (Fig. 3), but without statistical signi¢cance.None had uninhibited sphincter relaxation or detrusor-sphincter dyssynergia. Only one patient showed a minimumamount of post-void residuals (40 ml). There was no correla-tion between the changes of urodynamic parameters withage, sex, duration of the disease, or ADAS-cog score.

DISCUSSION

Central cholinergic agents are widely used in the treatmentof cognitive decline in AD.However, there are no urodynamicdata available focusing the e¡ect of such drugs on the LUTfunction to our knowledge.This is the ¢rst report to show thatdonepezil hydrochloride could ameliorate cognitive functionwithout serious adverse e¡ects on the LUT function in thepatients with AD. As regards the changes in urodynamic para-meters in the present study, detrusor overactivity appeared tobe augmented after the donepezil treatment. Although done-pezil may facilitate cholinergic neurotransmission mostly inthe central nervous system, common adverse e¡ects of done-pezil, such as nausea and abdominal discomfort, have beenattributed to the peripheral nervous system (PNS) [Rogerset al., 1998; Shinotoh et al., 2001]. Therefore, the increasedbladder contraction is reasonably attributed to the PNS e¡ectsas seen with other cholinergic drugs. However, our patientswith AD showed a slight increase in the bladder capacity,

which can not be explained by the PNS e¡ects alone.Although it is unknown to what extent central cholinergic cir-cuit may participate in the regulation of micturition, recentexperimental studies showed that lesions in the nucleusbasalis Mynert in the basal forebrain (central cholinergicnucleus projecting ¢bres to the frontoparietal cortex) give riseto decreased bladder capacity [Komatsu et al., 2000]. In ad-dition, improved cognitive status and alertness may welllead to proper initiative to hold urine in the patients. CentralAchE inhibitors including donepezil hydrochloride, there-fore, may have complex e¡ects on the LUT function. Sincethe number of our patients was small and without any control,this is a pilot study, and further clari¢cation of the pharmaco-mechanisms of donepezil on the LUT function is needed.

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Fig. 3. Bladder capacities. Pre: Before donepezil treatment; post,

after donepezil treatment. Horizontal bars indicate average values.

Urodynamic Assessment of Donepezil Hydrochloride in PatientsWith Alzheimer’s Disease 275