Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease

AIM: We investigated differences in the prevalence and severity of 10 neuropsychiatric and behavioral symptoms according to apolipoprotein E (APOE) genotype and dementia severity in Alzheimer disease (AD). METHODS: Neuropsychiatric and behavioral symptoms of 110 AD patients were assessed using the Neuropsychatric Inventory. Dementia severity was assessed using the Mini Mental State Examination (MMSE). RESULTS: There were 27 APOE-epsilon4-negative patients, 65 heterozygous patients and 18 homozygous patients. There was a significant association between the number of APOE epsilon4 alleles and prevalence and severity of neuropsychiatric and behavioral symptoms that was mainly attributable to delusions and agitation/aggression, which were more common and severer among homozygous APOE epsilon4 carriers. In addition, the presence of hallucinations, anxiety, apathy and aberrant motor behavior increased with deteriorating MMSE score, independently of APOE epsilon4 status. CONCLUSIONS: The present study showed that the APOE epsilon4 genotype modifies neuropsychiatric and behavioral phenotype in AD. In particular, it was shown that delusions and agitation/aggression were more common and severer among homozygous APOE epsilon4 carriers than among heterozygous or APOE-epsilon4-negative patients.     

The persistence of neuropsychiatric symptoms in dementia: the Cache County Study

OBJECTIVE: To estimate the 18-month persistence of neuropsychiatric symptoms in dementia in a population-based sample, and to compare the severity of neuropsychiatric symptoms at baseline to the severity at 18-month follow-up. METHODS: A population-based sample of 329 residents of Cache County, Utah, diagnosed with dementia was rated on the Neuropsychiatric Inventory (NPI). Of the 204 participants with neuropsychiatric symptoms at baseline (defined as total NPI score >0), NPI data were obtained approximately 18 months later on 117 who were alive and available for follow-up. RESULTS: Eighty-one percent of those with neuropsychiatric symptoms at baseline (defined as total NPI score>0) continued to have at least one symptom at follow-up. Sixty-seven percent of participants with a clinically significant total NPI score (defined as > or = 4) at baseline continued to have a clinically significant total NPI score at follow-up. Among the ten neuropsychiatric domains assessed at baseline, delusions persisted in 65.5% of individuals, followed by depression (58.3%), and aberrant motor behavior (55.6%), while hallucinations and disinhibition persisted in only 25.0% and 11.1% respectively. In participants who were symptomatic at both baseline and follow-up, the mean severity scores at the two observation points were comparable in all ten neuropsychiatric domains. CONCLUSIONS: Neuropsychiatric symptoms in dementia overall were highly persistent. Among those in whom symptoms did persist, symptom severity a year and a half later appeared to be comparable.     

Neuropsychiatric symptoms in dementia-frequency, relationship to dementia severity and comparison in Alzheimer's disease, vascular dementia and frontotemporal dementia

Noncognitive behavioral and psychiatric disturbances are common in dementia and help in the clinical differentiation of the various subtypes. We studied the frequency of neuropsychiatric disturbances, their relationship to dementia severity and compared these disturbances in Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) using the 12-item Neuropsychiatric Inventory (NPI). A total of 98 patients (AD-44, VaD-31, FTD-23) were evaluated. All subjects were community dwelling at the time of evaluation. The three groups were comparable on global dementia severity and functional ability. All patients had clinically significant scores on the NPI with apathy, irritability and agitation being very common (>90% of patients). AD and VaD patients in Clinical Dementia Rating (CDR) stage 2 had significantly higher scores on the total NPI, agitation and disinhibition subscales compared to those in CDR stage 1. Mean scores in the domains of aberrant motor behavior, disinhibition and appetite/eating behavior differentiated FTD from AD and VaD. Neuropsychiatric disturbances in dementia appear to be universal with agitation, disinhibition and irritability being more frequent in the later stages. In this cohort disinhibition, aberrant motor behavior and appetite/eating disturbances could reliably differentiate AD and VaD from FTD. There were no significant differences between the neuropsychiatric profiles of AD and VaD.     

Neuropsychiatric differences between Parkinson's disease with dementia and Alzheimer's disease

OBJECTIVE: To compare the profile of neuropsychiatric symptoms in patients with Parkinson's disease with dementia (PDD) and patients with Alzheimer's disease (AD). DESIGN: Cross-sectional survey of a population-based sample of patients with PDD and AD patients matched for age, sex, and Mini-Mental State Examination (MMSE) score. METHOD: Patients were diagnosed according to published criteria for PD and AD. The diagnosis of dementia in PD was made according to DSM-III-R, and was based on clinical interview of the patient and a relative, psychometric testing (including MMSE, Dementia Rating Scale and tests assessing memory, executive functions and visuospatial functioning) and physical examination. The Neuropsychiatric Inventory (NPI) was administered to all patients. RESULTS: One or more psychiatric symptoms was reported in 95% of AD and 83% of PDD patients. Hallucinations were more severe in PD patients, while aberrant motor behavior, agitation, disinhibition, irritability, euphoria, and apathy were more severe in AD. In PDD, apathy was more common in mild Hoehn and Yahr stages, while delusions increased with more severe motor and cognitive disturbances. In PDD, only delusions correlated with the MMSE score. CONCLUSIONS: Neuropsychiatric symptoms are common and severe in patients with PDD, with important implications for the management of these patients. AD and PDD patients have different neuropsychiatric profiles, suggesting different underlying mechanisms. Cognitive impairment, psychopathology, and motor features progress independently in PDD patients Copyright 2001 John Wiley & Sons, Ltd.     

Frontotemporal dementia: behavioral symptoms and caregiver distress

OBJECTIVE: To discern behavioral problems that co-occur in frontotemporal dementia (FTD) patients, and to investigate the relation between behavioral clusters and the burden for caregivers. PATIENTS AND METHODS: Baseline data of 63 FTD patients and their respective caregivers were used to detect the behavioral clusters in the Neuropsychiatric Inventory (NPI) and the accompanying distress evoked in caregivers. To detect the clusters in behavior of the FTD patients, we performed multidimensional scaling (procedure: PROXSCAL). Multiple regression analysis was used to determine the association between behavior of patients and the distress experienced by caregivers. RESULTS: This was the first study that found behavioral clusters for FTD. Two behavioral clusters were found: agitation/psychosis (comprising delusions, hallucinations, irritability and agitation) and mood (made up of anxiety and depression). The remaining NPI domains (euphoria, disinhibition, aberrant motor behavior and apathy were found to be autonomous. After controlling for relevant confounding factors, caregiver distress was strongest related to agitation/psychosis, followed by mood. Disinhibition and aberrant motor behavior were mildly related to caregiver distress. Euphoria and apathy were not significantly related to distress. Caregivers of patients living at home were more distressed by the behavioral problems of the FTD patients than caregivers of hospitalized patients. DISCUSSION: The high prevalence of psychopathology in FTD patients and the associated caregiver distress was confirmed in this study. Clustering behavioral symptoms allows investigation of the relationship between structural or functional cerebral deficits and neuropsychiatric symptoms.     

Apolipoprotein epsilon4 advances appearance of psychosis in patients with Parkinson's disease

BACKGROUND: Psychosis is one of the most serious complications of advanced parkinsonism, but many patients are spared. The genetic factors predisposing to psychosis are unclear. OBJECTIVES: To assess the association between apolipoprotein E (APOE) polymorphism and the development of psychosis in patients with Parkinson's disease (PD). METHODS: Eighty-seven patients with advanced PD were assessed. Psychosis was diagnosed in 50 patients who manifested paranoid delusions, hallucinations without insight, or disorders of perception. Time of onset of psychosis was retrieved from the medical records and caregivers' recall. APOE genotype was determined by restriction enzyme digests of amplified alleles. Cox models of logistic regression and Kaplan-Meier survival curves were used to assess factors determining early development of psychosis. RESULTS: APOE epsilon3/epsilon4 allele was carried by 20 patients (14 with psychosis), epsilon2/epsilon3 by 11 patients (10 with psychosis), epsilon3/epsilon3 by 55 patients (25 with psychosis) and epsilon2/epsilon4 by one patient who had psychosis. The mean age of onset of PD symptoms was 60.0 +/- 12.5 years. The mean duration of motor symptoms at the onset of psychosis was 7.3 +/- 4.3 years for the 15 patients harboring an APOE epsilon4 allele and 10.1 +/- 6.2 years among those who did not carry APOE epsilon4 (n = 35). The APOE epsilon4 allele was significantly associated with earlier onset of psychosis (P < 0.05) when the age of onset of motor symptoms and presence of dementia were included in the Cox regression model. Carrying the APOE epsilon4 allele was a significant risk factor for earlier appearance of psychosis with a hazard ratio of 3.24 (95% CI 1.62-6.46) while dementia by itself did not increase the risk. CONCLUSION: Parkinson's disease patients who carry the APOE epsilon4 allele develop psychosis earlier.     

Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials.

OBJECTIVE: The authors explored the effect of galantamine on behavioral symptoms in Alzheimer disease (AD). METHODS: Data were pooled from 2,033 subjects with mild-to-moderate AD who had participated in one of three randomized, double-blind, placebo-controlled trials of 3-, 5-, and 6-month durations. Subjects included in this post hoc analysis had received treatment with either placebo (N=686) or galantamine (N=1347) in total daily doses of 16 mg, 24 mg, or 32 mg. Behavioral symptoms were measured on the 10-item Neuropsychiatric Inventory (NPI). Four symptom clusters were defined a priori: 1) delusions, hallucinations; 2) agitation, depression, anxiety, apathy, irritability; 3) disinhibition, elation, aberrant motor behavior; 4) hallucinations, anxiety, apathy, aberrant motor behavior. RESULTS: At endpoint, mean changes from baseline in NPI scores were significantly different between galantamine-treated subjects and placebo-treated subjects, favoring galantamine for several measures: total NPI, individual domains of agitation/aggression, anxiety, disinhibition, and aberrant motor behavior, and Clusters 1, 3, and 4. The magnitude of the effect sizes was small. CONCLUSIONS: In this pooled sample of more than 2,000 subjects with mild-to-moderate AD, those who received galantamine therapy experienced modestly better, but statistically significant, outcomes in their behavioral symptoms than placebo-treated subjects. The cluster of hallucinations, anxiety, apathy and aberrant motor behaviors may represent a specific group of cholinergic-responsive behavioral symptoms.     

The impact of neuropsychiatric symptoms of dementia on distress in family and professional caregivers in Singapore

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are a source of distress and burden for caregivers. This study attempts to determine the neuropsychiatric symptoms, demographic characteristics, and referral patterns of outpatients with dementia compared with patients admitted to the acute psychogeriatric wards of Woodbridge Hospital. We also assessed the impact of neuropsychiatric symptoms on distress in family and professional caregivers. METHOD: Eighty-five consecutive patients with a first-time diagnosis of dementia were recruited. They were assessed using the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D). The professional caregiver distress questions were rephrased to assess the "occupational disruptiveness" of behaviors in the nursing home version (NPI-NH). RESULTS: Neuropsychiatric symptoms were common and were positively correlated with caregiver distress. Family caregivers were significantly more distressed than professional caregivers over the delusion, agitation, depression and aberrant motor domains, although the severity of the behavioral disturbances reported was not higher in the sample. The median NPI scores for the agitation and disinhibition domains were significantly higher in the inpatient group, contrasting with a higher score for the depression domain among the outpatient group. CONCLUSIONS: This study highlights the prevalence of neuropsychiatric symptoms in dementia and illustrates the strong correlation between the severity of behavioral disturbances and caregiver distress.     

Behavioral and psychological symptoms of dementia characteristic of mild Alzheimer patients

In order to clarify the characteristics of Behavioral and Psychological Symptoms of Dementia (BPSD) in patients with mild Alzheimer's disease (AD), BPSD among the severities of Clinical Dementia Rating (CDR) in 74 patients with AD were compared using the Neuropsychiatric inventory (NPI). The result, when compared between mild (CDR = 0.5, 1) and moderate or severe (CDR = 2, 3) AD, was a significant difference in frequency of euphoria, disinhibition and aberrant motor behavior, but no significant difference was found in frequency of delusions, hallucinations, agitation, dysphoria, anxiety, apathy and irritability. In addition, a significant difference was found in the mean scores of the composite score for euphoria, apathy, disinhibition and aberrant motor behavior, but no significant difference was found in the mean scores of the composite score for delusions, hallucinations, agitation, dysphoria, anxiety and irritability. That is, the mild AD groups (CDR 0.5 or 1) had delusions, hallucinations, agitation, dysphoria, anxiety, apathy and irritability as frequently as the moderate or severe AD groups (CDR 2 or 3), and had the equivalent level of composite scores to the moderate or severe AD groups (CDR 2 or 3) in delusion, hallucination, agitation, dysphoria, anxiety and irritability. Therefore, it was supposed that psychotic symptoms (delusion, hallucination) and emotional symptoms (agitation, dysphoria, anxiety, irritability) are important BPSD in patients with mild AD as well as those with moderate or severe AD, and there are needs for health, welfare and medical services for these symptoms.     

APOE genotype, vascular risk factors, memory test performance and the five-year risk of vascular cognitive impairment or Alzheimer's disease

The APOE epsilon4 gene and poor memory test performance have each been associated with an increased risk of developing dementia, but the relationship between these risk factors in predicting dementia is unclear. We examined the multivariate effects of APOE genotype, memory test performance and vascular risk factors in predicting incident Alzheimer's disease (AD) and vascular cognitive impairment (VCI) in the Canadian Study of Health and Aging. Delayed free recall was measured by the Buschke Cued Recall Test (BCRT). The study sample included 223 people who were identified as having no cognitive impairment (NCI) and either APOE epsilon3/epsilon3 or epsilon3/epsilon4 genotypes at the baseline clinical assessment. After 5 years, 182 (82%) still had NCI, 21 developed VCI (9%) and 20 AD (9%). Multivariate analyses demonstrated that APOE epsilon4 increased the risk of AD (OR, 3.48; CI, 1.15-10.48) but not VCI (OR, 0.89; CI, 0.24-3.27). Vascular risk factors increased the risk of VCI (OR, 2.18; CI, 1.36-3.51) but not AD (OR, 0.68; CI, 0.38-1.20). Lower BCRT scores conferred an increased risk of both VCI (OR, 1.75; CI, 1.27-2.42) and AD (OR, 1.86; CI, 1.29-2.67) but attenuated the APOE epsilon4 effect in AD. VCI and AD have different risk profiles and outcomes, but subtle memory difficulties may be an early feature of both.     

Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study

BACKGROUND: Neuropsychiatric symptoms are nearly universal in dementia, yet little is known about their longitudinal course in the community. OBJECTIVE: To estimate point and 5-year period prevalence of neuropsychiatric symptoms in an incident sample of 408 dementia participants from the Cache County Study. METHODS: The Neuropsychiatric Inventory assessed symptoms at baseline and at 1.5 years, 3.0 years, 4.1 years, and 5.3 years. Point prevalence, period prevalence and mean symptom severity at each time point were estimated. RESULTS: Point prevalence for delusions was 18% at baseline and 34-38% during the last three visits; hallucinations, 10% at baseline and 19-24% subsequently; agitation/aggression fluctuated between 13% and 24%; depression 29% at baseline and 41-47% subsequently; apathy increased from 20% at baseline to 51% at 5.3 years; elation never rose above 1%; anxiety 14% at baseline and 24-32% subsequently; disinhibition fluctuated between 2% and 15%; irritability between 17% and 27%; aberrant motor behavior gradually increased from 7% at baseline to 29% at 5.3 years. Point prevalence for any symptom was 56% at baseline and 76-87% subsequently. Five-year period prevalence was greatest for depression (77%), apathy (71%), and anxiety (62%); lowest for elation (6%), and disinhibition (31%). Ninety-seven percent experienced at least one symptom. Symptom severity was consistently highest for apathy. CONCLUSIONS: Participants were most likely to develop depression, apathy, or anxiety, and least likely to develop elation or disinhibition. Give converging evidence that syndromal definitions may more accurately capture neuropsychiatric co-morbidity in dementia, future efforts to validate such syndromes are warranted.     

Agitation in Alzheimer's disease is a manifestation of frontal lobe dysfunction

OBJECTIVES: (1) To investigate the prevalence and characteristics of agitation in patients with Alzheimer's disease (AD) and other forms of dementia; (2) to explore the association between agitation and other clinical variables, including disease severity, functional impairment and other neuropsychiatric symptoms, and (3) to determine the predictors of agitation. METHODS: Data for 427 men and women with dementia from outpatient clinics of the University of California, Los Angeles Alzheimer's Disease Center were analyzed. There were 277 patients with AD, 43 with vascular dementia, 47 with mixed dementia, 45 with frontotemporal dementia and 15 with dementia with Lewy bodies. Patients were evaluated with the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Functional Activities Questionnaire (FAQ), neuropsychological tests and the Caregiver Appraisal instrument. SPSS10 was utilized for statistical analysis. RESULTS: There was no difference in agitation subscale scores among patients with dementia of various etiologies. In patients with AD, there was increased prevalence of agitation with increasing dementia severity. Agitation contributed substantially to caregiver burden and impact. There was a significant correlation between the FAQ and the NPI agitation subscale score after adjusting for MMSE scores. Delusion, disinhibition and irritability subscale scores in AD patients were correlated with agitation across disease severity. Subscale scores of frontally mediated behaviors including irritability, delusions and disinhibition predicted most of the variance in agitation levels. CONCLUSION: Agitation is common in AD and other dementias and has a marked impact on caregivers. It is related to dementia severity and to specific types of associated psychopathology implicating frontal lobe dysfunction. The present study is the largest and most comprehensive assessment of agitation reported. The data suggest that agitation in AD is a frontal lobe syndrome. Frontal lobe dysfunction may predispose AD patients to agitation by exaggerating behavioral responses to many types of coexisting psychopathology or environmental provocations.     

Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study

OBJECTIVE: To examine, in an exploratory analysis, the association between vascular conditions and the occurrence of neuropsychiatric symptoms (NPS) in a population-based sample of incident Alzheimer's disease (AD). METHODS: The sample consisted of 254 participants, identified through two waves of assessment. NPS were assessed using the Neuropsychiatric Inventory. Prior to the onset of AD, data regarding a history of stroke, hypertension, hyperlipidemia, heart attack or coronary artery bypass graft (CABG), and diabetes were recorded. Logistic regression procedures were used to examine the relationship of each vascular condition to individual neuropsychiatric symptoms. Covariates considered were age, gender, education, APOE genotype, dementia severity, and overall health status. RESULTS: One or more NPS were observed in 51% of participants. Depression was most common (25.8%), followed by apathy (18.6%), and irritability (17.7%). Least common were elation (0.8%), hallucinations (5.6%), and disinhibition (6.0%). Stroke prior to the onset of AD was associated with increased risk of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p = 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was associated with increased risk of delusions (OR = 2.34, p = 0.02), anxiety (OR = 4.10, p = 0.002), and agitation/aggression (OR = 2.82, p = 0.01). No associations were observed between NPS and diabetes, hyperlipidemia, heart attack or CABG, or overall health. CONCLUSIONS: Results suggest that a history of stroke and hypertension increase the risk of specific NPS in patients with AD. These conditions may disrupt neural circuitry in brain areas involved in NPS. Findings may provide an avenue for reduction in occurrence of NPS through the treatment or prevention of vascular risk conditions.     

Neuropsychiatric Symptoms and Global Functional Impairment along the Alzheimer's Continuum

Background/Aims: Neuropsychiatric symptoms in Alzheimer's disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3-year period in older normal control (NC), mild cognitive impairment (MCI) and mild AD dementia subjects. Methods: Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer's Disease Neuroimaging Initiative study underwent cognitive and behavioral assessments over 3 years. Results: Greater hallucinations, anxiety and apathy were associated with greater global functional impairment at baseline, while the presence of hallucinations and apathy at baseline was associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep and appetite. Conclusions: These results suggest that increased baseline hallucinations, apathy and anxiety are associated with current and future disease progression in AD.     

APOE and the risk of PD with or without dementia in a population-based study

OBJECTIVE: To study the association between APOE genotype and PD with or without dementia. METHODS: The study formed part of the Rotterdam Study, a prospective, population-based cohort study on the frequency, etiology, and prognosis of chronic diseases. The cohort examined for PD consisted of 6,969 independently living or institutionalized inhabitants from a suburb of Rotterdam, the Netherlands, aged 55 years or older. All participants were screened at baseline (1990 to 1993) and at follow-up (1993 to 1994) for symptoms of parkinsonism by study physicians; screen positives received a diagnostic workup by a neurologist. RESULTS: APOE genotyping was available for 107 PD patients (26 with and 81 without dementia) and 4,805 non-PD control subjects. The presence of at least one epsilon2 allele significantly increased the risk of PD (OR = 1.7; 95% CI, 1.0 to 2.8). When we looked separately for demented and nondemented PD patients as compared with nonparkinsonian controls, APOE did not appear to be associated with PD without dementia, but both the epsilon2 and the epsilon4 allele increased the risk of PD with dementia (OR = 5.6; 95% CI, 2.0 to 15.2 and OR = 3.6; 95% CI, 1.3 to 9.9). The risk of dementia for epsilon4 allele carriers was not significantly different for persons with or without PD. However, the epsilon2 allele strongly increased the risk of dementia in patients with PD (interaction p < 0.007). CONCLUSIONS: In the elderly the APOE-epsilon2 allele increases the risk of PD and, in particular, the risk of PD with dementia.     

Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia

OBJECTIVE: The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS). METHOD: Fourteen male carriers of the FMR1 premutation who had clinical manifestations of the FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI), formal cognitive testing, and genetic analysis. RESULTS: Males with FXTAS had significantly higher total NPI scores (p < .004) and significantly higher scores on the agitation/aggression (p < .004), depression (p < .004), apathy (p < .004), disinhibition (p < .004), and irritability (p < .004) scales, compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. CONCLUSIONS: The neuropsychiatric manifestations of FXTAS, based on this preliminary report, appear to cluster as a fronto-subcortical dementia. Clinicians encountering patients with clinical dementia with motor symptoms suggesting FXTAS should consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status.     

Association of apolipoprotein E genotype and Alzheimer disease in African Americans

BACKGROUND: Alzheimer disease (AD) is the most frequent cause of dementia. Even though the incidence of AD in the African American population is similar to or higher than that in persons of European descent, AD in African Americans is understudied. Identification of genetic risk factors in African Americans is essential for understanding the etiology of AD. OBJECTIVE: To determine the effect of apolipoprotein E (APOE) genotype on the risk of AD in elderly African Americans. DESIGN: Population-based longitudinal study of AD. SETTING: Indianapolis, Ind. PARTICIPANTS: African Americans 65 years and older. MAIN OUTCOME MEASURES: APOE genotype and diagnosis of AD. RESULTS: The APOE genotype was determined in 1822 samples. Of these, 690 were clinically evaluated: 318 were normal, and 162 had a diagnosis of AD. The presence of APOE epsilon4 was significantly associated with increased risk of AD (epsilon3/epsilon4: OR, 2.32; 95% confidence interval [CI], 1.41-3.82; and epsilon4/epsilon4: OR, 7.19; 95% CI, 3.00-17.29, compared with the epsilon3/epsilon3 genotype). There was also a significant protective effect with APOE epsilon2 (epsilon2/epsilon2 and epsilon2/epsilon3: OR, 0.42; 95% CI, 0.20-0.89). CONCLUSIONS: These findings are in marked contrast to the lack of association between APOE and AD in the Ibadan, Nigeria, sample of this project. These results suggest that other genetic factors and different environmental influences may play a role in the risk for AD in individuals of African ancestry.     

An exploratory study of the efficacy and safety of yokukansan for neuropsychiatric symptoms in patients with Parkinson’s disease

The present study examined the efficacy and safety of yokukansan (YKS) in neuropsychiatric symptoms in patients with Parkinson’s disease (PD) using the neuropsychiatric inventory (NPI). Twenty-five patients with PD (M:F 14:11; age 72 years) were enrolled and treated with YKS (7.5 g/day) for 12 weeks. The NPI was assessed at 0, 4, 8, 12 and 16 weeks. The patient’s motor function and progression were evaluated using the Unified PD Rating Scale part III (UPDRS-III) and Hoehn and Yahr scale, respectively. The serum potassium concentration (sK) and all adverse events were recorded. The median NPI total score significantly decreased from 12 points at baseline to 4.0 points at 12 weeks (p = 0.00003). Within each NPI subscale, significant improvements were observed in hallucinations, anxiety and apathy. These symptoms tended to worsen after the completion of YKS treatment. Delusions, agitation, depression, euphoria, disinhibition, aberrant motor activity tended to improve but irritability showed no change. The median NPI subtotal scores, positive symptoms (delusions–hallucinations–irritability) significantly decreased (p = 0.01660) and negative symptoms (anxiety–apathy) significantly decreased (p = 0.00391). Both UPDRS-III and the Hoehn and Yahr scale showed no significant change. sK decreased mildly from 4.26 ± 0.30 to 4.08 ± 0.33 mEq/L. Two patients showed hypokalemia lower than 3.5 mEq/L without any corresponding symptoms; two patients showed listlessness and one patient showed drug eruption. Each recovered after discontinuation of YKS. YKS improved neuropsychiatric symptoms associated with PD, including hallucinations, anxiety and apathy without severe adverse events and worsening of Parkinsonism.     

Prevalence and clinical correlates of neuropsychiatric symptoms in dementia

The purpose of this research was to assess the frequency and severity of neuropsychiatric and behavioral symptoms and to examine the association between preexisting medical conditions and specific neuropsychiatric symptoms in demented individuals. We studied 211 demented subjects (87.7 percent male) who were participants in epidemiological studies of dementia. Using the Neuropsychiatric Inventory (NPI), we assessed the frequency and severity of neuropsychiatric symptoms. We collected medical history information during a structured telephone interview. Our analyses focused on determining prevalence of neuropsychiatric symptoms by dementia diagnosis and severity. We also examined the association of history of head injury, alcohol abuse, and stroke with development of neuropsychiatric symptoms. We found that neuropsychiatric symptoms were common, with approximately three-fourths of the subjects exhibiting at least one symptom during the preceding month. Apathy (39.3 percent), agitation (31.8 percent), and aberrant motor behavior (31.1 percent) were the most frequent symptoms. Frequency and severity of symptoms were similar for the all-dementia and Alzheimer's disease-only groups, neuropsychiatric symptoms varied by severity of dementia, but generally not in a consistent ordinal pattern. History of alcohol abuse, head injury, or stroke was associated with presence of specific neuropsychiatric symptoms in dementia. While psychiatric symptoms are common in dementia, they also vary by type and severity of dementia. The finding that certain medical conditions may increase risk for specific types of neuropsychiatric symptoms expands our knowledge of the natural history of dementia and should improve management of dementia in medically ill patients. Our results may also shed light on mechanisms that underlie neuropsychiatric symptoms.     

Impact of behavioral subsyndromes on cognitive decline in Alzheimer’s disease: data from the ICTUS study

Behavioral and psychological symptoms of dementia (BPSD) represent common manifestations among patients affected by Alzheimer’s disease (AD). Some reports have recently classified BPSD into specific clusters/subsyndromes exploring the internal structure of the Neuropsychiatric Inventory (NPI). We evaluated whether specific behavioral subsyndromes are associated with worsening cognitive function. Mild to moderate AD patients were recruited from the cohort of the Impact of Cholinergic Treatment USe (ICTUS) study. Neuropsychiatric symptoms were classified in three subsyndromes, identified at baseline, grouping different combinations of NPI items: (1) “psychotic” (“delusions” and/or “hallucinations”); (2) “affective” (“agitation” and/or “depression” and/or “anxiety” and/or “irritability”); and (3) “behavioral” (“euphoria” and/or “apathy” and/or “disinhibition” and/or “aberrant motor behavior”). Mixed model analyses were performed to measure six-monthly changes in the ADAS-Cog score over a follow-up of 2 years, according to these subsyndromes. All analyses were stratified according to AD severity as defined by the Clinical Dementia Rating (CDR). A total of 1,375 AD subjects were recruited. No NPI cluster was found to significantly (p < 0.05) affect the rate of cognitive decline across the 3 CDR classes. Our results suggest that the cognitive course of AD is not substantially influenced by the presence of specific neuropsychiatric phenotypes. Further studies are needed to extend the present findings and identify possible biological and clinical bases for behavioral subsyndromes.