# IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type

Authors: Noriko Sato; Akinori Ueki; Hideo Ueno; Hidetaka Shinjo; Yoshio Morita
Journal: Current Gerontology and Geriatrics Research
 (2008)

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## Abstract

Insulin degrading enzyme (IDE) degrades amyloidβ (Aβ), which may inhibit the accumulation of Aβ in a brain affected with dementia of Alzheimer's type (DAT). A decrease in the activity of IDE results in changes in glucose utilization in the brain, which could affect the cognitive and psychiatric symptoms of DAT. We investigated a possible association of IDE gene polymorphism and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for IDE and apolipoprotein E (ApoE) was determined in 207 patients with mild DAT and 215 controls. The occurrence of BPSD was demonstrated using the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). IDE gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of affective disturbance through the course of mild DAT, regardless of the presence of an ApoE ε4 allele. The present data could be the result of a small sample size. Further investigations using larger samples are thus required to clarify the correlation between IDE gene polymorphism, susceptibility to DAT, and emergence of BPSD.


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## Body

## 1. Introduction

Dementia of Alzheimer’s type (DAT) is a progressive
degenerative disorder in which the behavioral and psychological symptoms of
dementia (BPSD) are unavoidable. These symptoms constitute a great burden not
only on the patients, but also on their families and caregivers [1]. The stress
levels of caregivers may be reduced by predicting the occurrence of DAT and the
development of DAT-associated BPSD.The characteristic causes of neurological pathogenesis in
DAT are amyloid plaque deposition and neurofibrillary abnormalities in the
brain. Amyloid plaque is made up of amyloidβ (Aβ) proteins, which are formed
by the proteolysis of amyloid precursor protein. Excessive production and
insufficient clearance of Aβ lead to its extracellular deposition as plaque.
One way in which Aβ metabolism can fail is through hyperinsulinemia, caused by
the increase of insulin resistance through aging, because insulin stimulates Aβ
secretion to the extracellular space. One enzyme that regulates Aβ is insulin
degrading enzyme (IDE) [2–5].IDE is concentrated in the cytoplasm—and even more so
in the peroxisomes in liver, kidney, muscle, and brain cells—and it plays a
key role in degrading many important peptides [6–8]. Therefore,
not only DAT but also type 2 diabetes mellitus (DM) are linked to IDE [9, 10],
and DM is reported to promote the incidence of DAT [11].Other studies have already shown that IDE is linked to DAT.
Neurological investigations have found that the expression of IDE is reduced in
the brains of patients with DAT [12]. Several genetic linkage studies have
discovered the existence of a susceptibility locus for Alzheimer’s disease on
chromosome 10 [13–15]. The IDE
gene, located near the distal end of linkage region (10q23–q25), is an
attractive candidate for involvement in these phenotypes [16–19].
However, conflicting negative results have been reported [20–26].In our study, we analyzed SNPrs1999764, which is located in
the intron 1 of the IDE gene and which occurs as the consequence of a mutation
from thymine (T) to cytosine (C). We used this SNP because it is more
frequently polymorphic in the Japanese population than other SNPs [23]. This SNP has not been shown to result in a clear functional change,
but intronic SNP generally caused a change
in the expression of the protein and it affects the quantity and function of the
gene. Therefore, the possible roles of this SNP may lead to a reduction in IDE
activity and could be regarded as genetic determinants of predisposition and
the development of DAT-associated psychopathology.We investigated the relationship between IDE gene
polymorphism and the occurrence of DAT, the development of DAT-associated BPSD,
and BPSD in patients with sporadic mild DAT, independent of apolipoprotein E
(ApoE)ε4 status.An improved understanding of the relationship between DAT
and IDE gene polymorphism (including the presence of the ApoEε4 allele which
is considered to be a risk factor for sporadic DAT) could allow us to predict
the occurrence of DAT and the incidence of BPSD by detecting individual
polymorphisms in the gene for IDE. This would reduce the burdens on patients,
their families, and their caregivers, and would also help to provide more
appropriate care to patients in the future.


## 2. Materials and Methods

### 2.1. Subjects

All patients were collected prospectively from outpatients
of the Department of Neuropsychiatry, Hyogo College of Medicine. Two hundred
and seven subjects (73.5±8.2 years, 64 male/143 female) with mild DAT met the
NINCDS-ADRDA criteria for probable Alzheimer’s disease and were assigned to
stage 4 on the functional assessment staging (FAST) scale [27]. Each patient
received a cognitive assessment using the mini-mental state examination (MMSE) at
the time of DAT diagnosis. Functional assessments included the disability assessment
for dementia (DAD), which evaluates instrumental and basic activities of daily
living [28]. Mean (±standard deviation) duration of follow-up was 2.2±0.7 years
until DAT reached a moderate degree, defined as FAST stage 5. According to the
FAST scale, this duration of follow-up was consistent with the typical duration
of mild dementia in the clinical progression of DAT [27]. All patients were
receiving donepezil hydrochloride. During the mild stage of DAT, prevalence of
BPSD was determined in semistructured interviews with the subjects’ caregivers using
the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) at the
time of DAT diagnosis, then checked once a month to obtain information about only
the presence, not the magnitude, of paranoid and delusional ideation, hallucinations,
activity disturbance, aggressiveness, diurnal rhythm disturbance, affective
disturbance, and anxieties and phobias. We excluded patients with any history
of psychiatric hospitalization or use of medication for psychiatric problems at
any time before the first evaluation, as well as patients with other forms of
dementia such as dementia with Lewy bodies. The prevalence of BPSD was 90 DAT
patients (43.5%) at time of diagnosis, but all patients were free of
pharmacological treatment for BPSD. Forty-three patients who were treated with
pharmacological agents for the management of BPSD during follow-up were
excluded from the study. However, the data taken from these patients before
their pharmacological treatment began were enrolled in the study. The flow
chart of the progress through the study is depicted in Figure 1.Figure 1
Study flow chart. MMSE:
Mini-Mental State
Examination; FAST: Functional
Assessment Staging; DAD: Disability Assessment for Dementia; BEHAVE-AD: Behavioral
Pathology in Alzheimer’s Disease Rating Scale.We also collected 215 control subjects (72.1±8.6 years; t =
1.672, P  =  .0953, 85 male/130 female;  χ2=3.428, P  =  .0641) whose age and gender were matched. They were interviewed to exclude
individuals with a history or evidence of abuse, neurological disease or
psychiatric disorders and recruited from the general community or from among
medical and care staff volunteers in hospitals or health service facilities. The
presence of normal general cognitive function in these subjects was identified
by a score of greater than 27 on the MMSE.These interviews and diagnoses were performed by experienced
psychiatrists who were experts for elderly patients with cognitive disorders. The
patients were followed by the same psychiatrists.This study was approved by the ethics committee of the Hyogo
College of Medicine. We gave all subjects, who were native speakers of
Japanese, a sufficient explanation for the purpose of the study and obtained
their voluntary and written informed consent. In the case of DAT, we also gave
this explanation to the legal guardian.


### 2.2. Genotyping Method

We took blood from all subjects, injected it into
EDTA-containing tubes, and extracted genomic DNA from those samples using an
Easy DNA kit (TALENT, Trieste,
Italy). We
examined IDE gene polymorphism using a polymerase chain reaction restriction
fragment length polymorphism (PCR-RFLP) method. In other words, we amplified
the target DNA fragment by PCR, using the primers reported by Boussaha et al.
[21], and digested it with Alw26I (Fermentas Life Sciences, Ontario, Canada)
restriction enzyme. The DNA sequences possessing a T allele were not recognized
by Alw26I; those possessing a C allele were recognized. We also analyzed ApoE
polymorphism, which has been found to be a serious risk factor for a sporadic
DAT onset [29].


### 2.3. Statistics

We evaluated the results among the groups byχ2 test
for enumerated data with no ordered relationship, while Student’s t-test
was used for averaged data. For all comparisons, values of P  <  .05
were considered statistically significant. In comparisons between polymorphisms
and the evaluation of each symptom according to BEHAVE-AD, when we obtained
significant results by χ2 testing, we required a stricter
statistical significance in accordance with the Bonferroni correction.


## 2.1. Subjects

All patients were collected prospectively from outpatients
of the Department of Neuropsychiatry, Hyogo College of Medicine. Two hundred
and seven subjects (73.5±8.2 years, 64 male/143 female) with mild DAT met the
NINCDS-ADRDA criteria for probable Alzheimer’s disease and were assigned to
stage 4 on the functional assessment staging (FAST) scale [27]. Each patient
received a cognitive assessment using the mini-mental state examination (MMSE) at
the time of DAT diagnosis. Functional assessments included the disability assessment
for dementia (DAD), which evaluates instrumental and basic activities of daily
living [28]. Mean (±standard deviation) duration of follow-up was 2.2±0.7 years
until DAT reached a moderate degree, defined as FAST stage 5. According to the
FAST scale, this duration of follow-up was consistent with the typical duration
of mild dementia in the clinical progression of DAT [27]. All patients were
receiving donepezil hydrochloride. During the mild stage of DAT, prevalence of
BPSD was determined in semistructured interviews with the subjects’ caregivers using
the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) at the
time of DAT diagnosis, then checked once a month to obtain information about only
the presence, not the magnitude, of paranoid and delusional ideation, hallucinations,
activity disturbance, aggressiveness, diurnal rhythm disturbance, affective
disturbance, and anxieties and phobias. We excluded patients with any history
of psychiatric hospitalization or use of medication for psychiatric problems at
any time before the first evaluation, as well as patients with other forms of
dementia such as dementia with Lewy bodies. The prevalence of BPSD was 90 DAT
patients (43.5%) at time of diagnosis, but all patients were free of
pharmacological treatment for BPSD. Forty-three patients who were treated with
pharmacological agents for the management of BPSD during follow-up were
excluded from the study. However, the data taken from these patients before
their pharmacological treatment began were enrolled in the study. The flow
chart of the progress through the study is depicted in Figure 1.Figure 1
Study flow chart. MMSE:
Mini-Mental State
Examination; FAST: Functional
Assessment Staging; DAD: Disability Assessment for Dementia; BEHAVE-AD: Behavioral
Pathology in Alzheimer’s Disease Rating Scale.We also collected 215 control subjects (72.1±8.6 years; t =
1.672, P  =  .0953, 85 male/130 female;  χ2=3.428, P  =  .0641) whose age and gender were matched. They were interviewed to exclude
individuals with a history or evidence of abuse, neurological disease or
psychiatric disorders and recruited from the general community or from among
medical and care staff volunteers in hospitals or health service facilities. The
presence of normal general cognitive function in these subjects was identified
by a score of greater than 27 on the MMSE.These interviews and diagnoses were performed by experienced
psychiatrists who were experts for elderly patients with cognitive disorders. The
patients were followed by the same psychiatrists.This study was approved by the ethics committee of the Hyogo
College of Medicine. We gave all subjects, who were native speakers of
Japanese, a sufficient explanation for the purpose of the study and obtained
their voluntary and written informed consent. In the case of DAT, we also gave
this explanation to the legal guardian.


## 2.2. Genotyping Method

We took blood from all subjects, injected it into
EDTA-containing tubes, and extracted genomic DNA from those samples using an
Easy DNA kit (TALENT, Trieste,
Italy). We
examined IDE gene polymorphism using a polymerase chain reaction restriction
fragment length polymorphism (PCR-RFLP) method. In other words, we amplified
the target DNA fragment by PCR, using the primers reported by Boussaha et al.
[21], and digested it with Alw26I (Fermentas Life Sciences, Ontario, Canada)
restriction enzyme. The DNA sequences possessing a T allele were not recognized
by Alw26I; those possessing a C allele were recognized. We also analyzed ApoE
polymorphism, which has been found to be a serious risk factor for a sporadic
DAT onset [29].


## 2.3. Statistics

We evaluated the results among the groups byχ2 test
for enumerated data with no ordered relationship, while Student’s t-test
was used for averaged data. For all comparisons, values of P  <  .05
were considered statistically significant. In comparisons between polymorphisms
and the evaluation of each symptom according to BEHAVE-AD, when we obtained
significant results by χ2 testing, we required a stricter
statistical significance in accordance with the Bonferroni correction.


## 3. Results

### 3.1. Frequency of IDE Gene Polymorphism and Allele

The PCR-RFLP analysis showed that both the DAT and the
controls possessed the T allele more frequently than the C allele (genotype
distribution:χ2=3.006, P  =  .2225, allele frequency: χ2=6.167×10−5, P  =  .9937). When we ruled out the DAT patients and controls who carried
an ApoE ε4 allele, we got a similar result (genotype distribution: χ2=5.397, P  =  .0673, allele frequency: χ2=0.2991, P  =  .5845). We concluded that the incidence of DAT had no relevance to IDE gene
polymorphism and allele frequency, regardless of ApoE ε4 status (see Table 1).Table 1
Genotype
distributions and allele frequencies of IDE gene polymorphism in DAT patients
and controls after stratification according to ApoEε4 allele.
IDEIDE without ApoEε4DATControlsDATControlsGene polymorphismT/T (%)136 (65.7)136 (63.2)69 (67.0)113 (65.7)T/C (%)62 (30.0)75 (34.9)27 (26.2)56 (32.6)C/C (%)9 (4.3)4 (1.9)7 (6.8)3 (1.7)χ2 value3.0065.397P-value.2225.0673Allele frequencyT allele, %80.780.780.182.0C allele, %19.319.319.918.0χ2 value6.167  ×  10-50.2991P-value.9937.5845


### 3.2. Expression Frequency of BPSD

In the course of FAST stage 4, 145 DAT patients experienced
some BPSD (70.0%). The most frequently observed symptoms were affective
disturbance (32.9%), followed by anxieties and phobias (26.6%), aggressiveness
(24.2%), paranoid and delusional ideation (20.8%), activity disturbance
(15.0%), hallucinations (12.6%), and diurnal rhythm disturbance (10.1%). This
observation may differ from the results obtained by Reisberg et al. [30]. The
result indicated that we gave a referral center consultation service
that received many requests to see subjects
with BPSD.


### 3.3. BPSD Expression and IDE Gene Polymorphism

Among the patients with BPSD, we compared BPSD expression
and IDE gene polymorphism, but we could not get significance (genotype
distribution:χ2=3.144, P  =  .2077, allele frequency: χ2=3.363, P  =  .0667). We then excluded the patients who possessed an ApoE ε4 allele, but we
still could not get significance (genotype distribution: χ2=4.056, P  =  .1316, allele frequency:  χ2=3.363, P  =  .0667). The presence of an ApoE ε4 allele has been assumed to be involved in
the clinical expression of DAT, including BPSD. Scarmeas et al. [31] have
reported a possible association between the ApoE ε4 allele and BPSD in DAT
patients. We found that IDE gene polymorphism does not correlate with the
expression of BPSD in patients with or without ApoE ε4.


### 3.4. Analysis of BEHAVE-AD Items and IDE Gene Polymorphism

We tabulated the analysis of BEHAVE-AD items and IDE gene
polymorphism, which was evaluated during the course of mild stage of DAT (see Table2). We analyzed the associations between IDE gene polymorphism and the presence
of BPSD without the consideration of the magnitude of symptoms. We did not
investigate the difference in severity of a wide variety of BPSD according to
IDE gene polymorphism. After applying the Bonferroni correction, we obtained a
statistically significant result pertaining to the affective disturbance item.
The DAT patients who experienced some affective disturbance tended to have T/C
and C/C gene polymorphism and an increased incidence of the C allele. Except
for those carrying the ApoE ε4 allele, the number of subjects who exhibited T/C
or C/C gene polymorphism or who possessed the C allele was greater among those
patients with affective disturbance. The tendency toward affective disturbance
among DAT patients possessing the C allele of the IDE gene was independent of
their ApoE ε4 status (see Table 3). We also compared the T/T gene polymorphism
and C allele among the items of BEHAVE-AD, only affective disturbance was
significant with or without ApoE ε4 (χ2=14.07, P  <  .001;
χ2=15.75, P  <  .001).Table 2
χ2 analysis between
IDE genotype and BEHAVE-AD items.
BEHAVE-AD itemsIDEIDE without ApoEε4χ2P-valueχ2P-valueParanoid and delusional ideation0.56810.6156Hallucinations0.50480.9484Activity disturbance0.31790.4907Aggressiveness0.13060.3513Diurnal rhythm disturbance0.06180.0770Affective disturbance0.0018*0.0007**Anxieties and phobias0.38370.2044*P  =  .0126; **P  =  .0049 after Bonferroni correction.Table 3
Genotype distributions and allele
frequencies of IDE gene polymorphism in DAT patients with and without affective
disturbance after stratification according to ApoEε4 allele.
IDEIDE without ApoEε4DAT with affective disturbanceDAT without affective disturbanceDAT with affective disturbanceDAT without affective disturbanceGene polymorphismT/T (%)33 (48.5)102 (73.4)15 (41.7)53 (79.1)T/C (%)30 (44.1)33 (23.7)17 (47.2)11 (16.4)C/C (%)5 (7.4)4 (2.9)4 (11.1)3 (4.5)χ2  value12.6614.66P-value.0018*.0007**Allele frequencyT allele, %70.685.365.387.3C allele, %29.414.734.712.7χ2  value12.4814.01P-value.0004+.0002++*P  =  .0126; **P  =  .0049, +P  =  .0028; ++P  =  .0014 after Bonferroni correction.


### 3.5. Background and Preparation Factors of Affective Disturbance Expression

We set out to determine whether
any demographic, disease-related, or caregiver-related variables could be
affecting the incidence of affective disturbance. We categorized the DAT
patients by presence or absence of affective disturbance, and we compared
several variables across these groups, beginning with gender (χ2=2.588, P  =  .1077), education (t  =  0.7520, P  =  .4530), and cognitive
function by means of the MMSE (t  =  1.499,
P  =  .1354). Because social and physical factors such
as patient’s environment and caregiver contribute to the expression of BPSD, we
also compared assessment of ADL (t  =  1.627, P  =  .1053), incidence of physical complications (χ2=2.039, P  =  .1533) such as diabetes mellitus (χ2=0.0990, P  =  .7527) and hypertension (χ2=0.1040, P  =  .7471), receipt of social welfare
services (χ2=0.0980, P  =  .7547), age of the patient’s primary
caregiver (t  =  1.452, P  =  .1479), and the primary caregiver’s relationship to the patient (χ2=2.458, P  =  .4829). But in none of these cases
was there a statistically significant difference between DAT patients with
affective disturbance and DAT patients without (see Table 4).Table 4
Comparison of demographic,
disease-related, and caregiver-related variables of DAT patients with and
without affective disturbance at the time of diagnosis.
PatientsDAT with affective disturbanceDAT without affective disturbanceGender, male/female16/5248/91Education, years11.8±8.111.0±5.8Mean MMSE score ±SD19.7±3.219.0±3.5Mean DAD score ±SD80.0±6.977.9±9.6Physical problems, %29.439.6Diabetes mellitus, %7.48.6Hypertension, %16.218.0Receipt of social welfare services, %32.430.2Mean caregiver’s age ±SD, years56.8±14.660.2±14.9Relationship, %
(spouse/child/daughter-in-law/sibling)(47.1/33.8/16.2/2.9)(56.8/30.9/10.1/2.2)


## 3.1. Frequency of IDE Gene Polymorphism and Allele

The PCR-RFLP analysis showed that both the DAT and the
controls possessed the T allele more frequently than the C allele (genotype
distribution:χ2=3.006, P  =  .2225, allele frequency: χ2=6.167×10−5, P  =  .9937). When we ruled out the DAT patients and controls who carried
an ApoE ε4 allele, we got a similar result (genotype distribution: χ2=5.397, P  =  .0673, allele frequency: χ2=0.2991, P  =  .5845). We concluded that the incidence of DAT had no relevance to IDE gene
polymorphism and allele frequency, regardless of ApoE ε4 status (see Table 1).Table 1
Genotype
distributions and allele frequencies of IDE gene polymorphism in DAT patients
and controls after stratification according to ApoEε4 allele.
IDEIDE without ApoEε4DATControlsDATControlsGene polymorphismT/T (%)136 (65.7)136 (63.2)69 (67.0)113 (65.7)T/C (%)62 (30.0)75 (34.9)27 (26.2)56 (32.6)C/C (%)9 (4.3)4 (1.9)7 (6.8)3 (1.7)χ2 value3.0065.397P-value.2225.0673Allele frequencyT allele, %80.780.780.182.0C allele, %19.319.319.918.0χ2 value6.167  ×  10-50.2991P-value.9937.5845


## 3.2. Expression Frequency of BPSD

In the course of FAST stage 4, 145 DAT patients experienced
some BPSD (70.0%). The most frequently observed symptoms were affective
disturbance (32.9%), followed by anxieties and phobias (26.6%), aggressiveness
(24.2%), paranoid and delusional ideation (20.8%), activity disturbance
(15.0%), hallucinations (12.6%), and diurnal rhythm disturbance (10.1%). This
observation may differ from the results obtained by Reisberg et al. [30]. The
result indicated that we gave a referral center consultation service
that received many requests to see subjects
with BPSD.


## 3.3. BPSD Expression and IDE Gene Polymorphism

Among the patients with BPSD, we compared BPSD expression
and IDE gene polymorphism, but we could not get significance (genotype
distribution:χ2=3.144, P  =  .2077, allele frequency: χ2=3.363, P  =  .0667). We then excluded the patients who possessed an ApoE ε4 allele, but we
still could not get significance (genotype distribution: χ2=4.056, P  =  .1316, allele frequency:  χ2=3.363, P  =  .0667). The presence of an ApoE ε4 allele has been assumed to be involved in
the clinical expression of DAT, including BPSD. Scarmeas et al. [31] have
reported a possible association between the ApoE ε4 allele and BPSD in DAT
patients. We found that IDE gene polymorphism does not correlate with the
expression of BPSD in patients with or without ApoE ε4.


## 3.4. Analysis of BEHAVE-AD Items and IDE Gene Polymorphism

We tabulated the analysis of BEHAVE-AD items and IDE gene
polymorphism, which was evaluated during the course of mild stage of DAT (see Table2). We analyzed the associations between IDE gene polymorphism and the presence
of BPSD without the consideration of the magnitude of symptoms. We did not
investigate the difference in severity of a wide variety of BPSD according to
IDE gene polymorphism. After applying the Bonferroni correction, we obtained a
statistically significant result pertaining to the affective disturbance item.
The DAT patients who experienced some affective disturbance tended to have T/C
and C/C gene polymorphism and an increased incidence of the C allele. Except
for those carrying the ApoE ε4 allele, the number of subjects who exhibited T/C
or C/C gene polymorphism or who possessed the C allele was greater among those
patients with affective disturbance. The tendency toward affective disturbance
among DAT patients possessing the C allele of the IDE gene was independent of
their ApoE ε4 status (see Table 3). We also compared the T/T gene polymorphism
and C allele among the items of BEHAVE-AD, only affective disturbance was
significant with or without ApoE ε4 (χ2=14.07, P  <  .001;
χ2=15.75, P  <  .001).Table 2
χ2 analysis between
IDE genotype and BEHAVE-AD items.
BEHAVE-AD itemsIDEIDE without ApoEε4χ2P-valueχ2P-valueParanoid and delusional ideation0.56810.6156Hallucinations0.50480.9484Activity disturbance0.31790.4907Aggressiveness0.13060.3513Diurnal rhythm disturbance0.06180.0770Affective disturbance0.0018*0.0007**Anxieties and phobias0.38370.2044*P  =  .0126; **P  =  .0049 after Bonferroni correction.Table 3
Genotype distributions and allele
frequencies of IDE gene polymorphism in DAT patients with and without affective
disturbance after stratification according to ApoEε4 allele.
IDEIDE without ApoEε4DAT with affective disturbanceDAT without affective disturbanceDAT with affective disturbanceDAT without affective disturbanceGene polymorphismT/T (%)33 (48.5)102 (73.4)15 (41.7)53 (79.1)T/C (%)30 (44.1)33 (23.7)17 (47.2)11 (16.4)C/C (%)5 (7.4)4 (2.9)4 (11.1)3 (4.5)χ2  value12.6614.66P-value.0018*.0007**Allele frequencyT allele, %70.685.365.387.3C allele, %29.414.734.712.7χ2  value12.4814.01P-value.0004+.0002++*P  =  .0126; **P  =  .0049, +P  =  .0028; ++P  =  .0014 after Bonferroni correction.


## 3.5. Background and Preparation Factors of Affective Disturbance Expression

We set out to determine whether
any demographic, disease-related, or caregiver-related variables could be
affecting the incidence of affective disturbance. We categorized the DAT
patients by presence or absence of affective disturbance, and we compared
several variables across these groups, beginning with gender (χ2=2.588, P  =  .1077), education (t  =  0.7520, P  =  .4530), and cognitive
function by means of the MMSE (t  =  1.499,
P  =  .1354). Because social and physical factors such
as patient’s environment and caregiver contribute to the expression of BPSD, we
also compared assessment of ADL (t  =  1.627, P  =  .1053), incidence of physical complications (χ2=2.039, P  =  .1533) such as diabetes mellitus (χ2=0.0990, P  =  .7527) and hypertension (χ2=0.1040, P  =  .7471), receipt of social welfare
services (χ2=0.0980, P  =  .7547), age of the patient’s primary
caregiver (t  =  1.452, P  =  .1479), and the primary caregiver’s relationship to the patient (χ2=2.458, P  =  .4829). But in none of these cases
was there a statistically significant difference between DAT patients with
affective disturbance and DAT patients without (see Table 4).Table 4
Comparison of demographic,
disease-related, and caregiver-related variables of DAT patients with and
without affective disturbance at the time of diagnosis.
PatientsDAT with affective disturbanceDAT without affective disturbanceGender, male/female16/5248/91Education, years11.8±8.111.0±5.8Mean MMSE score ±SD19.7±3.219.0±3.5Mean DAD score ±SD80.0±6.977.9±9.6Physical problems, %29.439.6Diabetes mellitus, %7.48.6Hypertension, %16.218.0Receipt of social welfare services, %32.430.2Mean caregiver’s age ±SD, years56.8±14.660.2±14.9Relationship, %
(spouse/child/daughter-in-law/sibling)(47.1/33.8/16.2/2.9)(56.8/30.9/10.1/2.2)


## 4. Discussion

Although we hypothesized that there was a correlation
between IDE gene polymorphism and the susceptibility to DAT, our study has
shown that there is none. There is a correlation, however, between IDE gene
polymorphism and one symptom frequently associated with DAT.We began by examining earlier
studies about any substantial roles of IDE gene polymorphism in conferring
susceptibility to DAT. One research group has insisted that there was a
correlation between increased risk of DAT and IDE gene polymorphism in DAT patients without the ApoEε4 allele [16, 22]. Another report showed that DAT patients with the particular IDE gene
polymorphism and ApoE ε4 allele developed DAT [17], and others demonstrated a
relationship between increased risk of DAT and IDE gene polymorphism that was
independent of ApoE ε4 allele status [18, 19]. Other reports, to the contrary,
insisted that a particular SNP of the IDE gene was not pertinent to the risk of
DAT [20, 21, 23–26] (see Table 5). Our study could not identify any
relationship. The disagreement among the conclusions of all these authors is
probably due to the fact that different authors have examined different SNPs,
as well as the fact that the frequency of gene polymorphism and the
distribution of alleles vary among regions and races.
In fact, compared
with the SNP in our study, the Japanese population has a greater frequency of
the C allele in comparison with other races (NCBI Single Nucleotide
Polymorphism Cluster Report: rs 1999764).Table 5
Published studies of association
between DAT onset and IDE gene polymorphism.
Author (year)No. of DATNo. of controlAssociation between the risk of DAT and IDE gene polymorphismSNP (NCBI dbs.rs.no.)Abraham et al. [20]8694No association3758505, 464953,
4646954, 4646958Boussaha et al. [21]202186No association1999764, 1855916Edland et al. [16];
Edland [22]80118Association among DAT patients without ApoEε43758505, 4646954, 4646958Sakai et al. [23]240163No association1999764, 551266Bian et al. [17]210200Association among DAT patients with ApoEε44646953Nowotny et al. [18]12171257Association among DAT patients regardless of
ApoEε42251101Cellini et al.
[24]302164No association3758505, 4646958Ozturk et al.
[25]1012771No association2251101, 551266, 1832196Marlowe et al. [26]179516No association3758505, 4646954, 1832196, 4646958, 1544210Mueller et al. [19]444269Association among DAT patients11187007, 2149632,
7084090, 11187033, 11187033, 11187040,
11187060, 12412249, 7076966After reviewing the literature, we hypothesized that BPSD
expression was affected by IDE gene polymorphism. Because BPSD is used as a
measure of the severity of dementia but is assessed only at particular times
during the evaluation of DAT, the genetic predisposition could be missed if
BPSD was not being expressed at the time of the patient’s assessment and
assignment to a particular stage of DAT. Thus a longitudinal study of multiple
patients with the same degree of DAT was necessary.There is a significant discrepancy between the estimations
of prevalence of BPSD among patients with DAT in different stages [32]. Other
studies have shown that the frequency of BPSD may reach a peak during the mild
or moderate of the illness and may gradually decrease as the patient
deteriorates intellectually and physically [33–35]. Therefore, we assessed BPSD
expression among DAT patients at same stage. Our association study of BPSD used
repeated measurements across the course of mild DAT. We chose to study patients
diagnosed with mild DAT because it is comparatively easy to follow up with
individual patients through the whole period of mild dementia and to collect a
large number of patients for a longitudinal study. Our results showed that IDE
gene polymorphism had a significant relevance to BPSD, specifically to affective
disturbance. Nevertheless, no researcher has investigated this correlation
before us; therefore, we could not compare our results with others’.We hypothesized that IDE would have high affinity with
insulin and that its concentration could be regulated by glucose metabolism. An
earlier study found that glucose metabolism in one part of the cerebral cortex
decreased in DAT patients with BPSD, especially
those experiencing affective disturbance [36]. In addition, glucose utilization
decreases with aging [37]. Moreover,
there is a significant interaction between diabetes and depression [38], as well as between diabetes and
neurotransmitters such as serotonin [39]. This is  why only affective
disturbance showed a significant link to IDE gene polymorphism. Thus we can
conclude that glucose metabolism and the actions of some neurotransmitters can
affect BPSD expression.In this study, we tried to make a comparison of some
background and preparation factors such as physical complications, living
environment, and caregiver relationship between the DAT patients with affective
disturbance and those without. However, we could not obtain any clear results.
Although we hypothesized that glucose metabolism was associated with BPSD
expression, the incidence of diabetes mellitus did not correlation with the
incidence of BPSD. Perhaps this is because blood glucose, which is a primary
energy source for our brain, can be regulated by the
hypothalamic-pituitary-adrenal compensatory system even if glucose metabolism
becomes imbalanced [40]. As stated above, we could not obtain any significant
result, but if a regulated system gradually becomes unwell with aging, the
prevalence of diabetes mellitus can rise.Genetic, neurobiological, psychological, and social factors
can affect the expression of BPSD, but in our study, we have concluded that the
genetic and neurobiological factors have the greatest influence. For example,
the possession of the C allele of the IDE gene can cause patients to develop
BPSD such as affective disturbance. This result may prove that this SNP is in
linkage disequilibrium and works as a functional alteration of IDE, disrupting
the balance of glucose metabolism and neurotransmitter action. These changes
can lead to BPSD expression.The present data could be the result of small sample size,
small effect size of the polymorphisms, and the resultant limitation in
statistical power. The need for replication using larger samples might be
highlighted. However, previous studies investigating IDE polymorphisms for the
incidence of DAT have used subject population of 80 and 1217. Moreover,
positive results in 80 and 210 DAT patients have been published. Thus the
sample size in the present study is not unusually small (see Table5), and our findings should not be declared spurious on
that account.Throughout this study, we found it difficult to continue
examining the same patients due to their age and medical condition, and we
might not have been able to finish the study without the cooperation of
patients’ families. However, being able to predict the expression of certain
peripheral symptoms will enable caregivers to prepare the necessary care
systems and services, and will enable patients to make the necessary
adjustments to their living situations. Further investigations into the
correlation between IDE gene polymorphism, susceptibility to DAT, and emergence
of BPSD will help even more, so we intend to continue these studies in the
future.


## 5. Conclusions

IDE gene polymorphism is unlikely
to play a substantial role in conferring susceptibility to DAT, but it may be
involved in the development of affective disturbance through the course of mild
DAT, regardless of the presence of an ApoEε4 allele.



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*Source: 858759-2008-12-04.xml*