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| Memantine Abolishes Anticholinergic Activity in Patient with Alzheimer’s
Disease at Moderate Stage |
| Koji Hori1*, Kimiko Konishi1,2, Hiroi Tomioka1, Genshin Minegishi3, Masayuki Tani4, Hiroaki Tanaka3, Ryo Akita1, Sachiko Yokoyama1,
Tomoaki Oshio1 and Mitsugu Hachisu5 |
| 1Department of Psychiatry, Showa University Northern Yokohama Hospital, Kanagawa, Japan |
| 2Tokyo Metropolitan Tobu Medical Center for Persons with Developmental/Multiple Disabilities, Tokyo, Japan |
| 3Department of Psychiatry, Showa University Fujigaoka Hospital, Kanagawa, Japan |
| 4Department of Psychiatry, Showa University Karasuyama Hospital, Tokyo, Japan |
| 5Department of Clinical Psychopharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan |
| *Corresponding author: |
Koji Hori
Department of Psychiatry
Showa University
Northern Yokohama Hospital
35-1 Chigasakichuo, Tsuzukiku
Yokohama-City,
Kanagawa
224-8503, Japan
Tel: +81-45-949-7000
Fax: +81-45-949-7927
E-mail: kojihori@med.showa-u.ac.jp |
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| Received July 24, 2012; Accepted August 15, 2012; Published August 21, 2012 |
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| Citation: Hori K, Konishi K, Tomioka H, Minegishi G, Tani M, et al. (2012) Memantine
Abolishes Anticholinergic Activity in Patient with Alzheimer’s Disease at Moderate
Stage. J Alzheimers Dis Parkinsonism 2:108. doi:10.4172/2161-0460.1000108 |
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| Copyright: © 2012 Hori K, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| We already reported that anticholinergic activity (AA) can occur endogenously in patients with Alzheimer’s
disease (AD) at moderate stage. Since there is a possibility that AA might accelerate the pathologic changes of
AD (amyloid plaques and tau protein), it is important to establish treatment for abolishing AA. |
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| We report a 76-year-old man with Alzheimer’s disease (AD) at moderate stage, whose serum anticholinergic
activity (SAA) was positive when his memory disturbance, disorientation, apathy and aphasia were worsened.
His SAA disappeared after 3 months of treatment with memantine, antidementia agent with N-methyl-D-aspartate
(NMDA) receptor antagonist. At the same time his apathy and aphasia were ameliorated. |
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| We speculated that down-regulation of acetylcholine (ACh) caused the appearance of clinical symptoms
and the hyperactivity of NMDA at moderate stage, that the hyperactivity of NMDA caused the up-regulation of
inflammation, which caused AA and that the suppressions not only of the clinical symptoms and but also of the
inflammation were thought to be caused by the down-regulation of NMDA receptor by memantine, which caused
the ameliorations of some kinds of clinical symptoms and the disappearance of AA. We considered our patient
supported previous hypothesis that AA is generated endogenously in AD, SAA was a biological marker for rapid
progression of AD and memantine abolished AA in AD in moderate stage. |
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| Keywords |
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| Alzheimer’s disease; Serum anticholinergic activity;
Antidementia agent; Memantine; N-methyl-D-aspartate receptor
antagonist |
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| Abbreviations |
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| AA: Anticholinergic Activity; ACh: acetylcholine;
AD: Alzheimer’s Disease; BPSD: Behavioral and Psychological
Symptoms of Dementia; LBD: Lewy Body Disease; NMDA receptor:
N-methyl-D-aspartate receptor; SAA: Serum Anticholinergic Activity;
VCAA; Vicious Cycle of AA in AD |
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| Introduction |
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| We already reported that anticholinergic activity (AA) can occur
endogenously in patients with Alzheimer’s Disease (AD) [1]. Since
there is a possibility that AA might accelerate the pathologic changes
of AD (amyloid plaques and tau protein) [2], it is important to establish
treatment for abolishing AA. We also reported that down-regulation of
acetylcholine (ACh) production leads to an increase of inflammation
and an appearance of AA by means of up-regulation of N-methyl-Daspartate
(NMDA), and that Serum Anticholinergic Activity (SAA)
might be a biological marker of rapid progress of AD [3]. Therefore
we considered that memantine, an antidementia agent, using the
mechanism of antagonizing the NMDA receptor, abolished AA in AD
patients at moderate stage. |
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| We encountered a 76-year-old man with moderate AD who was
positive for SAA on the day before the prescription of memantine,
however, whose SAA became undetectable after three months of
treatment with memantine. We report the case and discuss why SAA
was detected on the day before the prescription of memantine and why
it became negative after three months of memantine treatment. Both
the patient and his wife gave written informed consent to publication
of this case report. |
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| Case Presentation |
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| The patient was a 76-year-old man who presented to the memory
clinic of our hospital (X year Y month). He had started to become
forgetful 2 years earlier. He showed visual-spatial agnosia (not knowing
a place of a lavatory), visual hallucination (water leaks from a lavatory),
disorientation of time (not understanding when it was in a day) from
X-1 year, and then immediate memory disturbance was worsened and
apathy appeared in X year. He has visited our hospital. The atrophy of
frontal and temporal lobes and the mild enlargement of lateral ventricle
were detected by CT. With a diagnosis of AD, he was prescribed with
donepezil 5 mg. After a treatment start, visual hallucinations were
ameliorated and his memory disturbance, disorientation and apathy
were not worsening for 2 Years. In X+2 years additional cares were
necessary for bathing, and urinary incontinence became outstanding.
He became more apathic and spoke meaninglessly. He was prescribed
with more 5 mg donepezil and fluvoxamine. However, these medications
were called off because of tremor and gait disturbances. The scores of
mini-mental state examination (MMSE) were 24 in X year, 26 in X+1
years, 24 and 20 in X+2 years, 17 in X+3 years and 11 in X+4 years, respectively. CT has showed the progression of brain atrophy since
X+2 years. At the same time his MMSE scores of memory disturbance
(registration and recall) and disorientation (time and place) were
worsening in X+2, X+3 and X+4 years. Moreover, he became more
apathic in X+3 and X+4 years and aphasia in X+4 years. He needed
care for bathing and toileting. Therefore we judged he has progressed
to moderate stage of AD and added memantine. After the prescription
of added memantine, his apathy was improved and he could speak
meaningful conversations again. In addition, the change of SAA was
2.38 nM on the X+4 years, but became under detectable level 3 months
later. There was no medication other than psychotropic ones being
prescribed for him and his physical state was not changed during this
period. Figure 1 shows the time course of clinical symptoms and signs
of this patient. |
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Figure 1: Time course of clinical symptoms in the patient. |
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| Discussion |
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| Since 2 years, his cognitive function has more rapidly declined
than before and his ADLs were also declined and needed cares for
bathing in X+4 years, we considered that the stage of AD in this patient
was at moderate stage when we prescribed memantine. CT findings
supported our diagnosis. We should consider Lewy Body Disease
(LBD) [4] because he showed the visual hallucination and fragility of
psychotropic medications. However, even in this case we consider that
LBD is related with AA from the clinical symptoms, signs and features
in LBD [5] and AA causes adverse effects on various neuropsychiatric
disorders including LBD. Therefore in this disorder we should
abolish AA. Moreover, when we prescribed memantine, not visual
hallucination but memory disturbances, disorientation, apathic and
aphasia were worsened. Since these features are characteristic of AD
[6], we considered that main pathology of this patient was AD at least
when we added memantine. However, because of fragility of psychotic
mecications, we should keep LBD in mind as his diagnosis. |
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| The origin of SAA in this patient is unknown. SAA (AA) was once
thought to be mainly induced by prescription medications, especially
medications with high AA, and by polypharmacy [7]. In our patient,
AA was not caused by medications, because his medications were
not changed during this period. Recently, it has been suggested that
AA might appear not only with exogenous manner, but also with an
endogenous manner and AA appeared by means of inflammation [8] and mental stress [9]. We reported a positive relationship between SAA
and clinical symptoms of AD patients [1,2]. Among 76 AD patients, 26
AD patients were positive for SAA [SAA (+)], the mean SAA value in the
SAA (+) group was 4.14 ± 2.70 nM and the remaining 50 patients were
negative [SAA (-)]. The SAA (+) group showed a significantly higher
numbers of prescribed psychotrophic medications, significantly lower
cognitive functions, and significantly more severe behavioral symptoms
such as delusions, hallucinations and diurnal rhythm disturbances.
Moreover, SAA (+) group showed significantly severe dementia stage.
The logistic regression analysis revealed that there were significant
correlations between SAA, delusion and diurnal rhythm disturbances.
We considered that AA was caused by psychotrophic medications and
caused behavioral symptoms. Moreover, we considered that because in
general we prescribe psychotropic medicines for the clinical psychiatric
symptoms of agitation and psychosis in AD. There might be the
cyclic relationships among these three factors. We termed this vicious
cycle “vicious cycle of AA in AD (VCAA)” and that there might be
endogenous AA. We reviewed that the down-regulation of ACh caused
not only cognitive dysfunction, especially memory disturbances,
but also the down-regulation of anti-inflammatory pathway, which
caused the up-regulation of inflammation, and that hyperactivity of
inflammation generated AA by way of the hyperactivity of the NMDA
receptors [3]. Therefore, the characteristic feature of AD is the downregulation
of ACh [10]. When the level of ACh becomes substantial, i.e.
at moderate stage, ACh generates endogenous manner in AD, which
causes the rapid progression of cognitive decline at moderate stage in
AD. We refer this “Alzheimer’s disease is progress by the mechanism of
its own” [3]. Moreover, we proposed a possibility that the SAA value
was a useful marker if the deterioration of AD pathology was rapidly
progressed at the moderate stage and that if SAA was positive, this
would suggest the rapid progression of AD and memantine, an open
channel uncompetitive NMDA receptor antagonist [11], should be used
for SAA positive AD patients to inhibit hyperactive NMDA receptor
system. Therefore, it should be considered that when SAA is detected in
AD, it’s time to prescribe memantine. |
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| In our patient, apathy and aphasia were ameliorated. At the same
time his MMSE scores of memory disturbance (registration and recall)
and disorientation (time and place) were worsening in X+2, X+3 and
X+4 years. Moreover, he became more apathic in X+3 and X+4 years
and aphasia in X+4 years. There are reports showing that memory
disturbance, disorientations, apathy and aphasia are related with AD
pathology, i.e. the down-regulations of ACh [6,12]. Therefore, we
considered that his clinical symptoms were gradually progressive until
X+2 years and rapidly since X+3 years. We also considered the rapid
progression of clinical symptoms was related with AA and if we had
measured in X+3 years, perhaps SAA had been positive. Moreover, it
is reported that memantine plus donepezil induced more amounts of
ACh than those expected by memantine alone plus those by donepezil
alone [13]. Therefore, we consider that in our patient enough ACh
was induced by memantine, which could suppress not only clinical
symptoms (apathy and aphasia) but also inflammation by means of upregulation
of anti-inflammatory pathway, by means of the up-regulation
of ACh and the down-regulation of NMDA receptor. The suppression
of inflammation leads to abolishment of AA [3,8]. This case supports
our hypothesis. We speculated that the deficiency of ACh was related to
the effects of memantine. |
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| However, the measurement of SAA is expensive and by way of
radioimmunoassay, needs the special institute. Therefore, we should
speculate the positiveness of SAA or AA through the relationships
between positive SAA and the clinical features. First, when the rate of decline of cognition became rapid than earlier, especially memory
disturbance, disorientation, apathy and aphasia, we should consider
that the SAA in this patient is positive [2]. Second, when the behavioral
and psychological symptoms of dementia (BPSD) such as delusion,
hallucination and diurnal rhythm disturbance appear [3], third, when
urinal obstruction, constipation or blurry vision appears in AD patient
[14], we should consider that SAA in this patient is positive. Especially,
BPSD are important because, the central cholinergic deficiency is
characterized by neuropsychiatric symptoms rather than by cognitive
dysfunctions [15,16]. |
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| Our report is only one case report. We observed only for a short
duration and we evaluated only the cognitive function using MMSE,
brain structure using CT and AA burden using SAA quantitatively.
We evaluated other clinical symptoms such as apathy and aphasia
qualitatively, i.e. clinical impression. Therefore we should conduct the
long-term observation of the disappearances of SAA by memantine
with large samples. We are now studying the longitudinal changes of
SAA in patients with AD. In this study we also investigate the effects
of antidementia agents (especially memantine) on the abolishment of
AA in AD. |
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| Conclusions |
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| We showed the possibility that memantine abolished AA in the
patient with AD at moderate stage using the case presentation. We
should conduct the long term observation of the disappearances of
SAA by memantine with large samples. |
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| References |
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