Baseline Neuropsychiatric Symptoms and the Risk of Incident Mild Cognitive Impairment: A Population-Based Study
Publication: American Journal of Psychiatry
Abstract
Objective
The authors conducted a prospective cohort study to estimate the risk of incident mild cognitive impairment in cognitively normal elderly (aged ≥70 years) individuals with or without neuropsychiatric symptoms at baseline. The research was conducted in the setting of the population-based Mayo Clinic Study of Aging.
Method
A classification of normal cognitive aging, mild cognitive impairment, and dementia was adjudicated by an expert consensus panel based on published criteria. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazards model, with age as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available for 1,587 cognitively normal persons who underwent at least one follow-up visit.
Results
The cohort was followed to incident mild cognitive impairment (N=365) or censoring variables (N=179) for a median of 5 years. Agitation (hazard ratio=3.06, 95% CI=1.89–4.93), apathy (hazard ratio=2.26, 95% CI=1.49–3.41), anxiety (hazard ratio=1.87, 95% CI=1.28–2.73), irritability (hazard ratio=1.84, 95% CI=1.31–2.58), and depression (hazard ratio=1.63, 95% CI=1.23–2.16), observed initially, increased risk for later mild cognitive impairment. Delusion and hallucination did not. A secondary analysis, limited in significance by the small number of study participants, showed that euphoria, disinhibition, and nighttime behaviors were significant predictors of nonamnestic mild cognitive impairment but not amnestic mild cognitive impairment. By contrast, depression predicted amnestic mild cognitive impairment (hazard ratio=1.74, 95% CI=1.22–2.47) but not nonamnestic mild cognitive impairment.
Conclusions
An increased incidence of mild cognitive impairment was observed in community-dwelling elderly adults who had nonpsychotic psychiatric symptoms at baseline. These baseline psychiatric symptoms were of similar or greater magnitude as biomarkers (genetic and structural MRI) in increasing the risk of incident mild cognitive impairment.
Mild cognitive impairment is the intermediate stage between normal cognitive aging and dementia (1–3). Individuals with mild cognitive impairment constitute a high-risk group because they develop dementia at a rate of 10%−15% per year compared with 1%−2% per year in the general population (4). Therefore, it is critical to understand the risk factors for mild cognitive impairment in order to intervene where possible.
Investigators have examined the outcome of incident dementia as determined by baseline neuropsychiatric symptoms in subjects with prevalent mild cognitive impairment (5–9). However, few studies have examined the risk of incident mild cognitive impairment in a cognitively normal cohort by neuropsychiatric status at baseline (10–12). Therefore, we conducted a population-based study to estimate the risk of incident mild cognitive impairment among cognitively normal individuals with or without baseline neuropsychiatric symptoms.
Method
Setting
The Mayo Clinic Study of Aging is a population-based study (13) designed to estimate the prevalence (14) and incidence (15) of mild cognitive impairment in elderly individuals in Olmsted County, Minnesota. Briefly, October 1, 2004, was selected as the prevalence date, and elderly individuals were recruited using a stratified random sampling from the target population of nearly 10,000 elderly people residing in Olmsted County (16). After complete description of the study, written informed consent was obtained. The study was conducted with the approval of the institutional review boards of the Mayo Clinic and Olmsted Medical Center in Rochester, Minnesota.
Cognitive Evaluation
Each participant underwent the following three face-to-face evaluations: 1) neurological evaluation by a physician, 2) risk factor assessment by a nurse or study coordinator, and 3) neuropsychological testing that was interpreted by a neuropsychologist. The interview by the nurse or study coordinator included administration of the Clinical Dementia Rating Scale (17) to the participant and to an informant. The neurological evaluation was performed by a physician and included administration of the Short Test of Mental Status (18), medical history review, and a complete neurological examination.
Neuropsychological testing was performed to assess four cognitive domains: 1) memory (assessed with the Logical Memory-II and Visual Reproduction-II [delayed recall for both] subtests from the Wechsler Memory Scale-Revised and with the Auditory Verbal Learning Test [delayed recall] [19–22]); 2) executive function (assessed with the Trail Making Test, Part B [23], and the Digit Symbol Substitution subtest from WAIS-R); 3) language (assessed with the Boston Naming Test [24]) and category fluency task [25]); and 4) visuospatial skills (assessed with the Picture Completion and Block Design from WAIS-R). The raw neuropsychological test scores were transformed to age-adjusted scores and were scaled to have a mean of 10 and a standard deviation of 3 in reference to normative data of Mayo’s Older Americans Normative Studies (26). Cognitive domain scores were obtained for each participant. Additionally, we calculated z scores in order to make comparisons across the four cognitive domains. Each person’s domain score was compared with the mean (standard deviation) from Mayo’s Older Americans Normative Studies. Thus, a z score ≥1.0 below the mean in a specific domain (e.g., memory) indicated memory impairment. However, the final decision about impairment in any cognitive domain was made during the weekly consensus panel of research team members that included physicians, neuropsychologists, and research nurses.
Mild Cognitive Impairment Criteria
We used the following revised Mayo Clinic criteria for mild cognitive impairment: 1) cognitive concern expressed by a physician, an informant, a participant, or nurse; 2) cognitive impairment in one or more domains (executive function, memory, language, or visuospatial); 3) normal functional activities; and 4) absence of dementia (27, 28). Participants with mild cognitive impairment could have a Clinical Dementia Rating Scale score of 0 or 0.5; however, the final diagnosis was not based exclusively on the clinical dementia rating but rather on all available data. The diagnosis of normal cognition, mild cognitive impairment, dementia, or Alzheimer’s disease was made by an expert consensus panel of physicians, psychologists, and nurses based on published criteria (1, 13, 28–30). The panel met once per week and reviewed three independent sources of data (i.e., the clinical data collected by behavioral neurologists and physicians of other specialties with expertise in dementia and mild cognitive impairment, neuropsychological data collected by psychometrists who are supervised by neuropsychologists, and nursing data gathered by research nurses) (13).
Mild Cognitive Impairment Subtypes
Participants that met criteria for mild cognitive impairment were further classified as having either the amnestic or the nonamnestic form of the disorder based on whether memory domain was impaired or not. Additionally, participants were further classified as having single- or multiple-domain impairment according to the number of domains that were impaired (27) (e.g., an individual with impairment of the memory domain only as defined by a z score ≥1.0 below the mean would be classified to have amnestic mild cognitive impairment, single-domain type, whereas an individual with impairments in both memory and executive function would be classified as having amnestic mild cognitive impairment, multiple-domain type). Furthermore, an individual with impairment in executive function only would be classified as having nonamnestic mild cognitive impairment, single-domain type. If both executive function and language were impaired, then the person would be classified as having nonamnestic mild cognitive impairment, multiple-domain type (Figure 1).
FIGURE 1. Mild Cognitive Impairment Criteria and Subtypesa
a Adapted/modified with permission from Petersen RC, “Mild Cognitive Impairment” [Continuum 2004; 10:9–28]. Copyright © 2004 American Academy of Neurology.
Neuropsychiatric Assessment
We assembled a cohort of cognitively normal persons for whom Neuropsychiatric Inventory Questionnaire data were available. The exposed cohort consisted of cognitively normal persons with one or more neuropsychiatric symptoms at baseline. The outcome of interest was incident mild cognitive impairment as measured by modified Mayo Clinic criteria (27). The baseline administration of the Neuropsychiatric Inventory Questionnaire took place between October 1, 2004, and September 1, 2007. Previously, we reported the population-based prevalence of baseline neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging (31). For the present incidence study, individuals with mild cognitive impairment were excluded at baseline. There were 1,640 cognitively normal persons in the cohort; however, data from the Neuropsychiatric Inventory Questionnaire were not available for 53 individuals. Thus, baseline data were available for 1,587 cognitively normal persons. Because 35 individuals died and 144 were lost to follow-up before the first follow-up visit, our analyses included a total of 1,408 participants.
The Neuropsychiatric Inventory Questionnaire was administered as a structured interview to a spouse or an informant of each study participant (32). The questionnaire is a shorter version of the Neuropsychiatric Inventory, which is a structured interview with established reliability and validity (33). Both the Neuropsychiatric Inventory and the Neuropsychiatric Inventory Questionnaire measure 12 emotional behavioral domains. We used the Neuropsychiatric Inventory Questionnaire because it was selected by the Uniform Data Set initiative of the National Institute on Aging (34).
The structured interview addressed 12 neuropsychiatric domains (agitation, delusion, hallucination, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and eating/appetite). The categorical outcome of the presence or absence of a neuropsychiatric symptom was documented and served as the exposure of interest of the study. Our primary goal was to determine the risk of incident mild cognitive impairment based on the presence or absence of baseline neuropsychiatric symptoms, not to determine the severity of neuropsychiatric symptoms. This goal was generated from our previous study derived from a clinical sample (10) (wherein we examined whether the presence or absence of baseline depression predicted the risk of incident mild cognitive impairment). Therefore, we sought to estimate a population-based risk of incident mild cognitive impairment by baseline presence or absence of neuropsychiatric symptoms, and we did not investigate the severity of neuropsychiatric symptoms.
Statistical Analyses
We conducted cohort analyses to determine the risk of incident mild cognitive impairment in cognitively normal individuals with or without a specific neuropsychiatric symptom at baseline. We computed hazard ratios and 95% confidence intervals using Cox proportional hazards model. The hazard ratio (95% confidence interval) for each neuropsychiatric symptom quantified the risk of developing incident mild cognitive impairment associated with a specific symptom at baseline after adjusting for age, sex, education, and medical comorbidity (35). The Charlson comorbidity index was calculated using Deyo’s method, wherein numeric values were assigned to comorbid medical conditions (e.g., a score of 1 was assigned for congestive heart failure, and a score of 6 was assigned for malignant tumor). A composite index was then calculated using Deyo’s method of the Charlson index (35, 36). Adjusting for age, sex, education, and medical comorbidity ensured that baseline neuropsychiatric symptoms predicted incident mild cognitive impairment over and above that which can be explained by these potential confounders. We also conducted secondary analyses for mild cognitive impairment subtypes by separating amnestic and nonamnestic impairment.
Statistical testing was performed at the conventional two-tailed alpha level of 0.05. All analyses were performed using SAS (SAS Institute, Cary, N.C.).
Results
Demographic characteristics of the sample are presented in Table 1. We followed the cohort of cognitively normal persons with available data from the Neuropsychiatric Inventory Questionnaire (N=1,587), to the outcome of incident mild cognitive impairment (N=365) or censoring events (death, N=35; lost to longitudinal follow-up, N=144), for a median of 5.0 years (interquartile range: 3.8–5.3). At baseline, there were differences in the frequency of neuropsychiatric symptoms by sex. There were more men than women in the agitation, apathy, irritability, and disinhibition groups, whereas there were more women than men in the depression, anxiety, and euphoria groups. The median age of the cohort members was 79.3 years (interquartile range: 75.0–83.4). The median level of education was 13 years (interquartile range: 12–16). The median number of comorbid medical conditions was 3 (interquartile range: 1–5), as measured by the Charlson comorbidity index.
| Characteristic | Total (N=1,408) | Depression Cohort (N=153) | Apathy Cohort (N=57) | Anxiety Cohort (N=66) | Agitation Cohort (N=33) | Irritability Cohort (N=96) | Appetite/Eating Cohort (N=67) | Motor Disturbance Cohort (N=7) | Nighttime Behaviors Cohorta (N=122) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | |
| Male | 704 | 50.0 | 72 | 47.1 | 33 | 57.9 | 28 | 42.4 | 20 | 60.6 | 62 | 64.6 | 3 | 64.2 | 4 | 57.1 | 68 | 55.7 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Age (years) | 79.3 | 75.0–83.4 | 79.8 | 75.2–83.6 | 79.1 | 76.2–82.7 | 81.3 | 75.9–83.9 | 79.1 | 75.3–82.7 | 79.3 | 75.1–83.3 | 81.5 | 76.9–84.3 | 79.4 | 72.8–83.1 | 80.2 | 75.2–82.6 |
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | |
| 70–79 | 741 | 52.6 | 79 | 51.6 | 31 | 54.4 | 30 | 45.5 | 20 | 60.6 | 52 | 54.2 | 27 | 40.3 | 4 | 57.1 | 61 | 50.0 |
| 80–91 | 667 | 47.4 | 74 | 48.4 | 26 | 45.6 | 36 | 54.5 | 13 | 39.4 | 44 | 45.8 | 40 | 59.7 | 3 | 42.9 | 61 | 50.0 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Education (years) | 13 | 12–16 | 12 | 12–15 | 13 | 12–16 | 13 | 12–16 | 13 | 12–16 | 13 | 12–16 | 13 | 12–16 | 12 | 12–17 | 13 | 12–16 |
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | |
| >12 | 801 | 56.9 | 74 | 48.4 | 29 | 50.9 | 36 | 54.5 | 20 | 60.6 | 50 | 52.1 | 38 | 56.7 | 3 | 42.9 | 70 | 57.4 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Charlson comorbidity index score | 3 | 1–5 | 3 | 2–5 | 4 | 2–8 | 3 | 2–5 | 4 | 2–6 | 3 | 1–5 | 4 | 2–7 | 2 | 2–6 | 3 | 2–6 |
| Time in study (years) | 5.03 | 5.3–8.0 | 4.5 | 2.9–5.2 | 4.1 | 2.7–5.2 | 4.5 | 3.2–5.2 | 4.3 | 3.1–5.2 | 4.6 | 2.9–5.2 | 4.5 | 3.6–5.3 | 4.1 | 3.9–5.3 | 5.1 | 3.1–5.3 |
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | |
| Incident mild cognitive impairment | 364 | 25.9 | 59 | 38.6 | 25 | 43.9 | 30 | 45.5 | 18 | 54.5 | 38 | 39.6 | 25 | 37.3 | 3 | 42.9 | 38 | 31.1 |
| Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | |
| Incidence rateb | 68 | 61–76 | 109 | 83–141 | 142 | 92–210 | 138 | 93–197 | 186 | 110–295 | 119 | 85–164 | 103 | 67–152 | 116 | 24–338 | 86 | 61–118 |
a
Nighttime behaviors assessment data were not available for 271 participants (the informant was unable to assess).
b
Data represent the age- and sex-standardized incidence rate of mild cognitive impairment (per 1,000 person-years).
We used person-years and survival analyses to calculate the incidence of mild cognitive impairment as predicted by baseline neuropsychiatric status. Thus, the age-sex standardized incidence rate of impairment was 68 per 1,000 person-years. After adjusting for age, sex, education, and medical comorbidity, we observed that the following baseline neuropsychiatric symptoms significantly predicted incident mild cognitive impairment: agitation (hazard ratio=3.06, 95% CI [confidence interval]=1.89–4.93, p<0.001); apathy (hazard ratio=2.26, 95% CI=1.49–3.41, p<0.001); anxiety (hazard ratio=1.87, 95% CI=1.28–2.73, p<0.001); irritability (hazard ratio=1.84, 95% CI=1.31–2.58, p<0.001); and depression (hazard ratio=1.63, 95% CI=1.23–2.16, p<0.001). Baseline delusion and hallucination did not predict incident impairment. There were substantial missing data for nighttime behavior (N=271). Therefore, the hazard ratio of nighttime behavior (1.46, 95% CI=1.03–2.06, p=0.03) should be interpreted with caution. Even though euphoria (hazard ratio=5.10, 95% CI=2.24–11.6, p<0.001) and disinhibition (hazard ratio=2.59, 95% CI=1.42–4.73, p=0.002) were significant predictors of incident impairment, these analyses were based on relatively small events. For example, there were only seven cognitively normal persons with baseline euphoria, of whom six developed incident mild cognitive impairment during subsequent follow-up. Similarly, there were only 22 cognitively normal persons with baseline disinhibition, of whom 11 developed incident impairment. Details of these findings are summarized in Table 2. The four most frequent neuropsychiatric symptoms at baseline were agitation, apathy, depression, and anxiety. At baseline, none of the participants had all four symptoms simultaneously. Only one participant had apathy, agitation, and anxiety at the same time at baseline. This person developed incident mild cognitive impairment during follow-up. Twenty-eight persons had comorbid depression and apathy, and 10 of these developed incident impairment during the subsequent follow-up.
| Characteristic | Disinhibition Cohort (N=22) | Euphoria Cohort (N=7) | Delusions Cohort (N=5) | Hallucinations Cohort (N=5) | ||||
|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | N | % | |
| Male | 12 | 54.5 | 3 | 42.9 | 2 | 40.0 | 3 | 60.0 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Age (years) | 80.3 | 76.2–84.3 | 81.3 | 78.0–82.0 | 80.9 | 78.4–83.5 | 86.2 | 82.7–86.8 |
| N | % | N | % | N | % | N | % | |
| 70–79 | 9 | 40.9 | 3 | 42.9 | 2 | 40.0 | 0 | 0.0 |
| 80–91 | 13 | 59.1 | 4 | 57.1 | 3 | 60.0 | 5 | 100.0 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Education (years) | 12 | 12–14 | 16 | 13–16 | 13 | 13–15 | 13 | 13–14 |
| N | % | N | % | N | % | N | % | |
| >12 | 10 | 45.5 | 6 | 85.7 | 4 | 80.0 | 4 | 80.0 |
| Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | Median | Interquartile Range | |
| Charlson comorbidity index score | 3.5 | 2–5 | 4 | 3–4 | 3 | 1–5 | 4 | 4–5 |
| Time in study (years) | 3.0 | 2.6–5.2 | 5.4 | 3.1–5.4 | 2.7 | 2.7–5.2 | 2.9 | 2.7–4.2 |
| N | % | N | % | N | % | N | % | |
| Incident mild cognitive impairment | 11 | 50.0 | 6 | 85.7 | 1 | 20.0 | 2 | 40.0 |
| Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | Incidence Rate | 95% CI | |
| Incidence ratea | 177 | 89–317 | 265 | 97–576 | 55 | 1–308 | 162 | 20–583 |
a
Data represent the age- and sex-standardized incidence rate of mild cognitive impairment (per 1,000 person-years).
Secondary Analyses
The primary outcome of interest was incident mild cognitive impairment. We conducted secondary analyses to examine whether neuropsychiatric symptoms differentially predicted amnestic or nonamnestic impairment (Tables 3 and 4). Euphoria (hazard ratio=11.3, 95% CI=3.44–37.2, p<0.001) and disinhibition (hazard ratio=5.18, 95% CI=2.24–12.0, p<0.001) were significant predictors of nonamnestic impairment. However, neither disinhibition nor euphoria significantly predicted amnestic impairment. Nighttime behavior was a significant predictor of nonamnestic impairment (hazard ratio=2.04, 95% CI=1.11–3.76, p=0.02) but not amnestic impairment. Depression predicted amnestic impairment (hazard ratio=1.74, 95% CI=1.22–2.47, p=0.002) but not nonamnestic impairment. Apathy predicted both amnestic (hazard ratio=1.93, 95% CI=1.09–3.41, p=0.02) and nonamnestic (hazard ratio=3.19, 95% CI=1.62–6.26, p<0.001) impairment.
| Psychiatric Symptom | Risk Adjusted for Age (Time Scale), Sex, and Education | Risk Additionally Adjusted for Medical Comorbidity | ||||
|---|---|---|---|---|---|---|
| Hazard Ratio | 95% CI | p | Hazard Ratio | 95% CI | p | |
| Total mild cognitive impairment | ||||||
| Depression | 1.68 | 1.27–2.22 | <0.001 | 1.63 | 1.23–2.16 | <0.001 |
| Apathy | 2.46 | 1.63–3.70 | <0.001 | 2.26 | 1.49–3.41 | <0.001 |
| Anxiety | 1.91 | 1.31–2.78 | <0.001 | 1.87 | 1.28–2.73 | 0.001 |
| Agitation | 3.13 | 1.94–5.05 | <0.001 | 3.06 | 1.89–4.93 | <0.001 |
| Irritability | 1.85 | 1.32–2.60 | <0.001 | 1.84 | 1.31–2.58 | <0.001 |
| Appetite/eating | 1.44 | 0.96–2.17 | 0.08 | 1.34 | 0.89–2.02 | 0.16 |
| Motor disturbance | 1.63 | 0.52–5.11 | 0.40 | 1.60 | 0.51–5.00 | 0.42 |
| Nighttime behaviorsa | 1.48 | 1.05–2.08 | 0.03 | 1.46 | 1.03–2.06 | 0.03 |
| Amnestic mild cognitive impairment | ||||||
| Depression | 1.75 | 1.23–2.48 | 0.002 | 1.74 | 1.22–2.47 | 0.002 |
| Apathy | 1.98 | 1.13–3.47 | 0.02 | 1.93 | 1.09–3.41 | 0.02 |
| Anxiety | 1.65 | 0.99–2.76 | 0.05 | 1.64 | 0.98–2.74 | 0.06 |
| Agitation | 2.18 | 1.07–4.44 | 0.03 | 2.16 | 1.06–4.41 | 0.03 |
| Irritability | 1.69 | 1.09–2.64 | 0.02 | 1.69 | 1.08–2.63 | 0.02 |
| Appetite/eating | 1.09 | 0.61–1.95 | 0.78 | 1.06 | 0.59–1.91 | 0.85 |
| Motor disturbance | 0.84 | 0.12–6.01 | 0.86 | 0.84 | 0.12–5.97 | 0.86 |
| Nighttime behaviorsa | 1.44 | 0.93–2.24 | 0.11 | 1.44 | 0.93–2.25 | 0.10 |
| Nonamnestic mild cognitive impairment | ||||||
| Depression | 1.26 | 0.68–2.31 | 0.46 | 1.18 | 0.64–2.16 | 0.60 |
| Apathy | 3.81 | 1.97–7.38 | <0.001 | 3.19 | 1.62–6.26 | <0.001 |
| Anxiety | 2.84 | 1.50–5.35 | 0.001 | 2.74 | 1.45–5.16 | 0.002 |
| Agitation | 5.14 | 2.46–10.7 | <0.001 | 4.92 | 2.36–10.3 | <0.001 |
| Irritability | 2.18 | 1.18–4.02 | 0.01 | 2.18 | 1.18–4.03 | 0.01 |
| Appetite/eating | 1.52 | 0.70–3.30 | 0.29 | 1.31 | 0.60–2.85 | 0.50 |
| Motor disturbance | 4.12 | 1.00–16.9 | <0.05 | 3.89 | 0.94–16.0 | 0.06 |
| Nighttime behaviorsa | 2.11 | 1.15–3.88 | 0.02 | 2.04 | 1.11–3.76 | 0.02 |
a
Nighttime behaviors assessment data were not available for 271 participants (the informant was unable to assess).
| Psychiatric Symptom | Risk Adjusted for Age (Time Scale), Sex, and Education | Risk Additionally Adjusted for Medical Comorbidity | ||||
|---|---|---|---|---|---|---|
| Hazard Ratio | 95% CI | p | Hazard Ratio | 95% CI | p | |
| Total mild cognitive impairment | ||||||
| Disinhibition | 2.60 | 1.42–4.75 | 0.002 | 2.59 | 1.42–4.73 | 0.002 |
| Euphoria | 5.07 | 2.23–11.5 | <0.001 | 5.10 | 2.24–11.6 | <0.001 |
| Delusions | 0.60 | 0.08–4.27 | 0.61 | 0.55 | 0.08–3.95 | 0.55 |
| Hallucinations | 1.57 | 0.39–6.37 | 0.52 | 1.48 | 0.37–5.99 | 0.58 |
| Amnestic mild cognitive impairment | ||||||
| Disinhibition | 1.49 | 0.55–4.01 | 0.43 | 1.48 | 0.55–4.00 | 0.44 |
| Euphoria | 2.42 | 0.59–9.84 | 0.22 | 2.41 | 0.59–9.83 | 0.22 |
| Delusions | 1.02 | 0.14–7.34 | 0.98 | 1.00 | 0.14–7.15 | 1.00 |
| Hallucinations | 1.32 | 0.18–9.52 | 0.78 | 1.30 | 0.18–9.34 | 0.80 |
| Nonamnestic mild cognitive impairment | ||||||
| Disinhibition | 5.22 | 2.26–12.0 | <0.001 | 5.18 | 2.24–12.0 | <0.001 |
| Euphoria | 10.7 | 3.27–35.1 | <0.001 | 11.3 | 3.44–37.2 | <0.001 |
| Delusionsa | 0.99 | 0.99 | ||||
| Hallucinations | 3.10 | 0.42–22.7 | 0.27 | 2.76 | 0.38–20.3 | 0.32 |
a
Values for hazard ratios and 95% confidence intervals were not applicable.
Discussion
We reported the population-based risk of incident mild cognitive impairment as predicted by baseline neuropsychiatric symptoms in cognitively normal persons. At baseline, there were sex differences in the frequency of neuropsychiatric symptoms (i.e., more men than women were observed to have agitation, apathy, irritability, and disinhibition, whereas more women than men were observed to have depression, anxiety, and euphoria). These findings were largely consistent with previously reported observations (e.g., a study conducted in Helsinki reported a slightly higher rate of apathy in men than in women [37]; a Japanese study reported that physical agitation but not verbal agitation was higher in men than in women [38]; several studies, including the Cache County Study [39] and large-scale epidemiological studies [40, 41], have reported that depression is higher in women than in men).
We observed that nonpsychotic symptoms strongly increased the risk for incident mild cognitive impairment. How do these neuropsychiatric symptoms compare with genetic, biomarker, and demographic predictors of incident mild cognitive impairment? Such comparisons are best done with studies that use methods that are similar, if not identical, to those of our study. Therefore, we compared our findings with the biomarker predictors of incident mild cognitive impairment reported by our colleagues who specialize in the imaging work of the Mayo Clinic Study of Aging. Our colleagues reported that the hazard ratio for hippocampal volume (as measured by brain MRI) in predicting incident impairment was 1.8 (95% CI=1.4–2.20) (42), whereas here we report that the hazard ratio for apathy in predicting incident impairment is 2.26 (95% CI=1.49–3.41), and it is even higher for agitation (3.06, 95% CI=1.89–4.93). This is an informative comparison because the difference in the strength of predicting incident mild cognitive impairment by a biomarker compared with a neuropsychiatric symptom cannot simply be attributed to methodological difference because both the imaging and neuropsychiatric research took place in the context of the Mayo Clinic Study of Aging. Similarly, the risk of incident mild cognitive impairment given exposure to baseline neuropsychiatric symptoms was as strong as, or even stronger than, the risk given exposure to apolipoprotein ε4 (10), comorbid medical conditions (43), or demographic variables, such as lower education (15).
Delusions and hallucinations did not predict incident mild cognitive impairment. Even though euphoria and disinhibition were significant predictors of incident impairment, their risk estimates were based on few participants. There were only seven cognitively normal persons with baseline euphoria, of whom six developed incident impairment. Similarly, there were 22 cognitively normal persons with baseline disinhibition, of whom 11 developed incident impairment. A secondary analysis showed that euphoria and disinhibition were significant predictors of nonamnestic but not amnestic impairment. Given the small number of participants that reported these symptoms, at best we can only hypothesize that disinhibition and euphoria at baseline in a cognitively normal elderly person may increase the risk of nonamnestic impairment that may progress to fronto-temporal dementia. Similarly, nighttime behavior was a significant predictor of nonamnestic but not amnestic impairment, and this may lead to progression of dementia with Lewy bodies (44).
Few studies have investigated the prediction of incident mild cognitive impairment by baseline neuropsychiatric symptoms (10–12). Most studies have examined the prediction of incident dementia by baseline neuropsychiatric symptoms (7, 45). The Sydney Memory and Ageing Study reported the prediction of cognitive impairment by baseline neuropsychiatric symptoms in 873 individuals aged 70–90 years (46). Consistent with our study, the investigators measured baseline neuropsychiatric symptoms using the Neuropsychiatric Inventory (34). They defined cognitive impairment by diagnostic category (prevalent mild cognitive impairment or incident dementia) or by neuropsychological performance. They followed the cohort of cognitively normal persons and individuals with prevalent mild cognitive impairment over a 2-year period to the outcomes of cognitive decline (defined as worse neuropsychological performance) or incident dementia. They observed that agitation and anxiety predicted cognitive decline (12). These investigators also observed that agitation, apathy, irritability, and anxiety were associated with prevalent impairment. A study examining the outcome of incident mild cognitive impairment by baseline neuropsychiatric symptoms would be ideal to compare with our study. The Chicago Health and Aging Project examined the outcome of incident mild cognitive impairment as predicted by baseline status of proneness to chronic psychological distress measured by the NEO Personality Inventory (47, 48). The investigators observed that a “distress prone” elderly person at baseline was 40% more likely to develop incident mild cognitive impairment than a person who reported to be less distress prone (11). The construct of chronic proneness to psychological distress is not identical to the neuropsychiatric construct as measured by the Neuropsychiatric Inventory Questionnaire; however, both instruments measured emotional behavior in a cohort of elderly persons that were recruited for cognitive research. Thus, we can suggest that emotional behavior at baseline in a cognitively normal person may be associated with increased risk of mild cognitive impairment.
We did not investigate the possible mechanisms linking baseline neuropsychiatric symptoms with incident mild cognitive impairment. Previously, we proposed possible explanations for the link between baseline depression and the outcome of incident mild cognitive impairment (10, 49). It is possible that baseline neuropsychiatric symptoms could be the noncognitive manifestation of the underlying neurodegenerative disorder (reverse causality). Alternatively, an underlying neuropathology may be causing both cognitive and emotional behavior manifestations (shared etiology model). The third possibility is that a synergistic interaction between neuropsychiatric symptoms and a biological factor (e.g., apolipoprotein ε4 genotype) may lead to clinical outcomes such as mild cognitive impairment.
Our study findings consist of several strengths. First, we conducted our study in a population-based setting involving a large cohort that was followed for several years. Thus, our findings are less prone to referral bias (50–52). Second, we were able to examine a spectrum of emotional behavior by investigating several neuropsychiatric symptoms as predictors of incident mild cognitive impairment. Third, we measured impairment using a face-to-face evaluation adjudicated by an expert consensus panel at a center that has a well established reputation for measuring mild cognitive impairment. On the other hand, our findings should be interpreted in light of some limitations. The Neuropsychiatric Inventory/Neuropsychiatric Inventory Questionnaire gathers information from an informant who is knowledgeable about the participant. In our sample, 90% of the informants were spouses. Even though such data have the advantage of being observed behaviors, the informant may not be able to recognize subtle signs. However, other studies (e.g., the Sydney Memory and Ageing Study) that used the Neuropsychiatric Inventory also reported similar results (e.g., agitation and anxiety predicted cognitive decline in both the Sydney study and our study). While our study’s goal of examining the presence or absence of a baseline neuropsychiatric symptom in predicting incident mild cognitive impairment addresses a clinically relevant question, it is also possible that factoring in severity of symptoms might have added more depth to our findings.
In summary, in this population-based study, we assembled a cohort of cognitively normal persons for whom we acquired baseline neuropsychiatric symptoms data. We then followed the cognitively normal cohort forward in time to the outcomes of incident mild cognitive impairment or censoring events. Nonpsychotic neuropsychiatric symptoms at baseline were significant positive predictors of incident mild cognitive impairment. Euphoria, disinhibition, and nighttime behavior predicted incident nonamnestic but not amnestic impairment. Psychotic symptoms (delusions and hallucinations) predicted neither amnestic nor nonamnestic impairment.
References
1.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303–308
2.
Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ; Alzheimer’s Disease Cooperative Study: Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 2004; 61:59–66
3.
Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer’s Disease Cooperative Study Group: Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352:2379–2388
4.
Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST; Report of the Quality Standards Subcommittee of the American Academy of Neurology: Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology 2001; 56:1133–1142
5.
Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart SA, Moll van Charante EP, van Gool WA; Alzheimer’s Disease Neuroimaging Initiative: Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer’s disease in non-depressed subjects. Dement Geriatr Cogn Disord 2012; 33:204–209
6.
Mitchell RA, Herrmann N, Lanctôt KL: The role of dopamine in symptoms and treatment of apathy in Alzheimer’s disease. CNS Neurosci Ther 2011; 17:411–427
7.
Palmer K, Di Iulio F, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Spalletta G: Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer’s disease: the role of depression and apathy. J Alzheimers Dis 2010; 20:175–183
8.
Rosenberg PB, Mielke MM, Appleby B, Oh E, Leoutsakos JM, Lyketsos CG: Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction. Int J Geriatr Psychiatry 2011; 26:364–372
9.
Ramakers IH, Visser PJ, Aalten P, Kester A, Jolles J, Verhey FR: Affective symptoms as predictors of Alzheimer’s disease in subjects with mild cognitive impairment: a 10-year follow-up study. Psychol Med 2010; 40:1193–1201
10.
Geda YE, Knopman DS, Mrazek DA, Jicha GA, Smith GE, Negash S, Boeve BF, Ivnik RJ, Petersen RC, Pankratz VS, Rocca WA: Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study. Arch Neurol 2006; 63:435–440
11.
Wilson RS, Schneider JA, Boyle PA, Arnold SE, Tang Y, Bennett DA: Chronic distress and incidence of mild cognitive impairment. Neurology 2007; 68:2085–2092
12.
Brodaty H, Heffernan M, Draper B, Reppermund S, Kochan NA, Slavin MJ, Trollor JN, Sachdev PS: Neuropsychiatric symptoms in older people with and without cognitive impairment. J Alzheimers Dis 2012; 31:411–420
13.
Roberts RO, Geda YE, Knopman DS, Cha RH, Pankratz VS, Boeve BF, Ivnik RJ, Tangalos EG, Petersen RC, Rocca WA: The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology 2008; 30:58–69
14.
Petersen RC, Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS, Boeve BF, Tangalos EG, Ivnik RJ, Rocca WA; The Mayo Clinic Study of Aging: Prevalence of mild cognitive impairment is higher in men. Neurology 2010; 75:889–897
15.
Roberts RO, Geda YE, Knopman DS, Cha RH, Pankratz VS, Boeve BF, Tangalos EG, Ivnik RJ, Rocca WA, Petersen RC: The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging. Neurology 2012; 78:342–351
16.
St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, Rocca WA: Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester epidemiology project. Am J Epidemiol 2011; 173:1059–1068
17.
Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43:2412–2414
18.
Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RC: The Short Test of Mental Status: correlations with standardized psychometric testing. Arch Neurol 1991; 48:725–728
19.
Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen RC, Kokmen E, Kurland LT: Mayo’s Older Americans Normative Studies: WAIS-R norms for ages 56 to 97. Clin Neuropsychol 1992; 6:1–30
20.
Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen RC, Kokmen E, Kurland LT: Mayo’s Older Americans Normative Studies: WMS-R norms for ages 56 to 94. Clin Neuropsychol 1992; 6:49–82
21.
Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen RC, Kokmen E, Kurland LT: Mayo’s Older Americans Normative Studies: updated AVLT norms for ages 56 to 97. Clin Neuropsychol 1992; 6:83–104
22.
Malec JF, Ivnik RJ, Smith GE, Tangalos EG, Petersen RC, Kokmen E, Kurland LT: Mayo’s Older Americans Normative Studies: utility of corrections for age and education for the WAIS-R. Clin Neuropsychol 1992; 6:31–47
23.
Reitan RM: Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958; 8:271–276
24.
Kaplan E, Goodglass H, Brand S: Boston Naming Test. Philadelphia, Lea and Febiger, 1983
25.
Lucas JA, Ivnik RJ, Smith GE, Bohac DL, Tangalos EG, Graff-Radford NR, Petersen RC: Mayo’s older Americans Normative Studies: category fluency norms. J Clin Exp Neuropsychol 1998; 20:194–200
26.
Ivnik R, Malec J, Smith G, Tangalos E, Petersen R, Kokmen E, Kurland L: Mayo’s Older Americans Normative Studies: WAIS-R, WMS-R, and AVLT norms for ages 56 through 97. Clin Neuropsychol 1992; 6:1–104
27.
Petersen RC: Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256:183–194
28.
Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC: Mild cognitive impairment: beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004; 256:240–246
29.
; American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994
30.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939–944
31.
Geda YE, Roberts RO, Knopman DS, Petersen RC, Christianson TJ, Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, Tangalos EG, Rocca WA: Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry 2008; 65:1193–1198
32.
Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, Lopez OL, DeKosky ST: Validation of the NPI-Q: a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000; 12:233–239
33.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308–2314
34.
Morris JC, Weintraub S, Chui HC, Cummings J, Decarli C, Ferris S, Foster NL, Galasko D, Graff-Radford N, Peskind ER, Beekly D, Ramos EM, Kukull WA: The Uniform Data Set (UDS): clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alzheimer Dis Assoc Disord 2006; 20:210–216
35.
Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–383
36.
Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45:613–619
37.
Hölttä EH, Laakkonen M-L, Laurila JV, Strandberg TE, Tilvis RS, Pitkälä KH: Apathy: prevalence, associated factors, and prognostic value among frail, older inpatients. J Am Med Dir Assoc 2012; 13:541–545
38.
Schreiner AS: Aggressive behaviors among demented nursing home residents in Japan. Int J Geriatr Psychiatry 2001; 16:209–215
39.
Steffens DC, Norton MC, Hart AD, Skoog I, Corcoran C, Breitner JC; Cache County Study Group: Apolipoprotein E genotype and major depression in a community of older adults. The Cache County Study. Psychol Med 2003; 33:541–547
40.
Kessler RC, McGonagle KA, Nelson CB, Hughes M, Swartz M, Blazer DG: Sex and depression in the National Comorbidity Survey, II: cohort effects. J Affect Disord 1994; 30:15–26
41.
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62:617–627
42.
Kantarci K, Weigand SD, Przybelski SA, Preboske GM, Pankratz VS, Vemuri P, Senjem ML, Murphy MC, Gunter JL, Machulda MM, Ivnik RJ, Roberts RO, Boeve BF, Rocca WA, Knopman DS, Petersen RC, Jack CR: MRI and MRS predictors of mild cognitive impairment in a population-based sample. Neurology 2013; 81:126–133
43.
Luck T, Riedel-Heller SG, Luppa M, Wiese B, Wollny A, Wagner M, Bickel H, Weyerer S, Pentzek M, Haller F, Moesch E, Werle J, Eisele M, Maier W, van den Bussche H, Kaduszkiewicz H; AgeCoDe Study Group: Risk factors for incident mild cognitive impairment: results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Acta Psychiatr Scand 2010; 121:260–272
44.
Molano J, Boeve B, Ferman T, Smith G, Parisi J, Dickson D, Knopman D, Graff-Radford N, Geda Y, Lucas J, Kantarci K, Shiung M, Jack C, Silber M, Pankratz VS, Petersen R: Mild cognitive impairment associated with limbic and neocortical Lewy body disease: a clinicopathological study. Brain 2010; 133:540–556
45.
Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE, Lyketsos CG: The association of neuropsychiatric symptoms in MCI with incident dementia and Alzheimer disease. Am J Geriatr Psychiatry 2013; 21:685–695
46.
Brodaty H, Heffernan M, Kochan NA, Draper B, Trollor JN, Reppermund S, Slavin MJ, Sachdev PS: Mild cognitive impairment in a community sample: the Sydney Memory and Ageing Study. Alzheimers Dement 2013; 9:310–317
47.
Bienias JL, Beckett LA, Bennett DA, Wilson RS, Evans DA: Design of the Chicago Health and Aging Project (CHAP). J Alzheimers Dis 2003; 5:349–355
48.
Costa PT, McCrae RR: Personality in adulthood: a six-year longitudinal study of self-reports and spouse ratings on the NEO Personality Inventory. J Pers Soc Psychol 1988; 54:853–863
49.
Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, Evans J, Lee M, Porsteinsson A, Lanctot KL, Rosenberg PB, Sultzer DL, Francis PT, Brodaty H, Padala PP, Onyike CU, Ortiz LA, Ancoli-Israel S, Bliwise DL, Martin JL, Vitiello MV, Yaffe K, Zee PC, Herrmann N, Sweet RA, Ballard C, Khin NA, Alfaro C, Murray PS, Schultz S, Lyketsos CG; Neuropsychiatric Syndromes Professional Interest Area of ISTAART: Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future. Alzheimers Dement 2013; 9:602–608
50.
Kokmen E, Ozsarfati Y, Beard CM, O’Brien PC, Rocca WA: Impact of referral bias on clinical and epidemiological studies of Alzheimer’s disease. J Clin Epidemiol 1996; 49:79–83
51.
Tsuang D, Kukull W, Sheppard L, Barnhart RL, Peskind E, Edland SD, Schellenberg G, Raskind M, Larson EB: Impact of sample selection on APOE epsilon 4 allele frequency: a comparison of two Alzheimer’s disease samples. J Am Geriatr Soc 1996; 44:704–707
52.
Szklo M, Nieto FJ: Epidemiology: Beyond the Basics, 2nd ed. Sudbury, Mass, Jones and Bartlett, 2007
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Received: 25 June 2013
Revision received: 17 December 2013
Accepted: 13 January 2014
Published online: 1 May 2014
Published in print: May 2014
Authors
Funding Information
Dr. Roberts has received funding from Abbvie Health Outcomes Research. Dr. Mielke receives funding from the Alzheimer’s Drug Discovery Foundation, the Driskill Foundation, the Michael J. Fox Foundation, and NIH. Dr. Pankratz has received grant support from the National Institute on Aging. Dr. Boeve has served as an investigator for clinical trials sponsored by Allon Pharmaceuticals, Cephalon, and GE Healthcare; he receives royalties from Cambridge University Press and has received honoraria from the American Academy of Neurology; he serves on the scientific advisory board of the Tau Consortium; and he receives research support from the Mangurian Foundation and the National Institute on Aging. Dr. Petersen has received funding from GE Healthcare, Genentech, Janssen Alzheimer Immunotherapy, Merck, Pfizer, and Roche. All other authors report no financial relationships with commercial interests.Supported by NIH grants K01 MH-068351, U01 AG006786, and K01 AG028573; National Institute on Aging grants P50 AG016574, U01 AG006786 (to Drs. Pankratz and Boeve), and RO1 AG032306 and RO1 AG041797 (to Dr. Boeve); the Mayo Clinic Career Transition Award RR024150; the Robert Wood Johnson Foundation (Harold Amos Scholar); the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program; and in part by the European Regional Development Fund (project FNUSA-ICRC, number CZ.1.05/1.1.00/02.0123), the Czech Ministry of Health (grant NT13434-4/2012), and the Mayo Clinic Center for Individualized Medicine.
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