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Objectives: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales. Design: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores. Setting: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively. Participants: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease. Measurements: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory – Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics. Results: Among the MCID was a decrease of four points (95% CI: −4.0 to −4.8) on the NPI-A, 0.56 points (95% CI: −0.47 to −0.65) on the DAIR, and three points on the AES-I (95% CI: −0.9 to −5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID. Conclusions: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales. [ABSTRACT FROM AUTHOR]

Objectives Caring for a spouse with Alzheimer's disease (AD) can elicit considerable distress but there are also positive moments. A growing body of work has examined caregivers' ambivalence in the care relationship and linked it to negative caregiver outcomes such as depression, but dyadic assessments of both parties' perspectives are missing. We examined ambivalence in both people with AD and their spousal caregivers, seeking to identify the correlates and well-being outcomes of such ambivalence in this unique context. Methods Participants included 72 couples managing early-stage AD. People with AD and spousal caregivers independently self-reported positive and negative relationship qualities (used to indirectly calculate their ambivalence) and life satisfaction. Caregivers reported both partners' demographic characteristics and their spouses' behavioral and psychological symptoms of dementia (BPSD), focusing on memory-related behaviors and psychological symptoms. Results Path analyses revealed that the number and frequency of psychological symptoms in people with AD were positively associated with their own and caregivers' ambivalence. Caregivers' distress ratings of memory-related behaviors and psychological symptoms were positively associated with their ambivalence. Greater ambivalence was associated with lower life satisfaction in both spouses. BPSD directly affected both spouses' life satisfaction but there were also indirect effects via ambivalence. Discussion This study utilizes a dyadic approach to assess ambivalence in dementia care. Findings reveal the conflicting emotions that couples experience as they cope with early-stage AD, identify sources of such ambivalence, and shed light on the development of dyadic interventions that can promote positive outcomes in both partners. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period.Methods: Twenty-three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearman's correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time.Results: The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%-83.9%) and inconsistent correlations between NPI assessments (e.g., range rs  = 0.20-0.57 for agitation, range rs  = 0.29-0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (rs  = 0.60, p < 0.001), but changes in NPI total scores were unrelated to changes in caregiver burden (rs  = 0.16, p = 0.20).Conclusions: We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations. [ABSTRACT FROM AUTHOR]

Background: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results.Objective: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1.Methods: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period.Results: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences.Conclusion: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view. [ABSTRACT FROM AUTHOR]

• Tg mouse models of AD show social withdrawal and depressive-like behaviours with age. • Tg mouse models of AD show early sleep-wake disturbances and increased aggression. • Tg mouse models of AD show mixed results concerning generalized apathy or anxiety. • Tg mouse models of AD are an important tool to study biological mechanisms of BPSD. Transgenic mouse models have been used extensively to model the cognitive impairments arising from Alzheimer's disease (AD)-related pathology. However, less is known about the relationship between AD-related pathology and the behavioural and psychological symptoms of dementia (BPSD) commonly presented by patients. This review discusses the BPSD-like behaviours recapitulated by several mouse models of AD-related pathology, including the APP/PS1, Tg2576, 3xTg-AD, 5xFAD, and APP23 models. Current evidence suggests that social withdrawal and depressive-like behaviours increase with progressive neuropathology, and increased aggression and sleep-wake disturbances are present even at early stages; however, there is no clear evidence to support increased anxiety-like behaviours, agitation (hyperactivity), or general apathy. Overall, transgenic mouse models of AD-related pathology recapitulate some of the BPSD-like behaviours associated with AD, but these behaviours vary by model. This reflects the patient population, where AD patients typically exhibit one or more BPSD, but rarely all symptoms at once. As a result, we suggest that transgenic mouse models are an important tool to investigate the pathology underlying BPSD in human AD patients. [ABSTRACT FROM AUTHOR]

A pangenome is composed of all the genetic variability of a group of individuals, and its application to the study of neurodegenerative diseases may provide valuable insights into the underlying aspects of genetic heterogenetiy for these complex ailments, including gene expression, epigenetics, and translation mechanisms. Furthermore, a reference pangenome allows for the identification of previously undetected structural commonalities and differences among individuals, which may help in the diagnosis of a disease, support the prediction of what will happen over time (prognosis) and aid in developing novel treatments in the perspective of personalized medicine. Therefore, in the present review, the application of the pangenome concept to the study of neurodegenerative diseases will be discussed and analyzed for its potential to enable an improvement in diagnosis and prognosis for these illnesses, leading to the development of tailored treatments for individual patients from the knowledge of the genomic composition of a whole population. • Pangenomics can detect undisclosed aspects of genetic variability in neurodegeneration. • The complexity of neurodegenerative diseases can be more easily disentangled with population-based information. • Personalized medicine can leverage knowledge from pan-omic methods to inform tailored treatments. • Identification of novel variability among subjects may improve diagnosis, prognosis, and care in neurodegeneration. [ABSTRACT FROM AUTHOR]

Objectives: Prior research and theories established the link between care environments and apathy. Yet, empirical evidence on how environmental stimulation impacts apathy is lacking. This study examined the association between environmental stimulation and apathy in nursing home residents with dementia.Design: This repeated-measure study analyzed 104 video observations of staff caregiver-resident interactions.Setting: 12 nursing homes.Participants: 63 unique staff caregiver-resident dyads that involved 42 caregivers and 44 residents with moderate to severe dementia.Measurements: Second-by-second behavioral coding using Noldus Observer software was conducted to assess apathy and environmental stimulation, using the Person-Environment Apathy Rating scale. The environment subscale includes six items: stimulation clarity, stimulation strength, stimulation specificity, interaction involvement, physical accessibility, and environmental feedback. The apathy subscale includes six items: facial expression, eye contact, physical engagement, purposeful activity, verbal tone, and verbal expression. Multilevel linear models were used for analysis.Results: Results showed that apathy was not associated with the overall quality of environmental stimulation but was significantly associated with stimulation specificity (coefficient = -2.23, p = 0.049). However, the association was not significant after controlling for resident characteristics (p = 0.082). In addition, higher levels of environmental feedback were associated with lower apathy levels (coefficient = -2.14, p = 0.001). The association remained significant after controlling for resident characteristics (coefficient = -1.65, p = 0.014).Conclusion: Findings reveal that when environmental stimulation is individually tailored and prompts engagement, residents are less apathetic. This study highlights the effect of environmental stimulation on apathy. Future research should explore interventions that modify environmental stimulation to reduce apathy and improve dementia care. [ABSTRACT FROM AUTHOR]

• Behavioral and psychological symptoms of dementia (BPSD) present in Alzheimer's disease. • Certain BPSD in Alzheimer's disease co-present and can be clustered into distinct domains. • Serotonergic system has been tied to cognitive decline and multiple BPSD domains. • This review summarizes the evidence for specific serotonergic system alterations in BPSD. Behavioral and Psychological Symptoms of Dementia (BPSD), present in almost 90% of patients with Alzheimer's Disease (AD), cause extensive impairment leading to reduced independence and inability to complete activities of daily living. Though BPSD includes a wide range of symptoms, such as agitation, aggression, disinhibition, anxiety, depression, apathy, delusions, and hallucinations. Certain BPSD in AD co-present and can be clustered into distinct domains based on their frequency of co-occurrence. As these BPSD are so pervasive in any stages of AD, the disease may be better characterized as a disorder of heterogeneous degenerative symptoms across a number of symptom domains, with the most prominent domain comprising memory and cognitive deficits. Importantly, there are no FDA-approved drugs to treat these BPSD, and new approaches must be considered to develop effective treatments for AD patients. The biogenic monoamine 5-hydroxytryptamine (5-HT), or serotonin, works as both a neurotransmitter and neuromodulator, which has been tied to cognitive decline and multiple BPSD domains. This review summarizes the evidence for specific serotonergic system alterations across some of the well-studied cognitive, behavioral, and psychiatric domains. Though differences in overall serotonergic transmission occur in AD, circuit-specific alterations in individual 5-HT receptors (5-HTRs) are likely linked to the heterogeneous presentation of BPSD in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by progressive cognitive decline, often associated with Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase inhibitors (ChEi) may attenuate cognitive decline and mitigate BPSD. The EVOLUTION group found that the switch from oral ChEi to transdermal rivastigmine patch formulation resulted in improvement/stabilization in the frequency of clinically relevant BPSD, but gender-specific subgroup analyses were not reported. Methods: Participants underwent Neuropsychiatric Inventory to assess the frequency and severity of neuropsychiatric symptoms at baseline and 3 and 6 months after the switch from oral ChEi to transdermal rivastigmine patch. A descriptive post hoc analysis was conducted to assess whether there were gender-based differences in BPSD profile during the 6 months after the switch. Results: The entire sample consisted of 475 patients, 274 women and 201 men. Women were on average slightly older and with poorer cognitive performance (60.6% of the women had moderate-AD, defined as Mini-Mental State Examination [MMSE] score of 10–17, vs. 43.8% of men). In mild-AD patients (MMSE score 18–26), the frequency of BPSD did not change significantly over time and an association was found between gender and depression (odds ratio; OR [95% confidence interval; CI] female vs. male = 3.32 [1.44–7.67]), anxiety (2.42 [1.23–4.79]), apathy (2.25 [1.07–4.70]), nighttime behavior disturbances (3.97 [1.66–9.49]), and appetite/eating abnormalities (2.39 [1.10–5.18]). Moderate-AD female patients had euphoria more frequently than male patients (OR [95% CI] female vs. male = 3.67 [1.25–10.74]). The frequency of delusions, anxiety, and irritability decreased during the first 3 months after the switch, independently of gender. Conclusion: Mild-AD women tended to suffer more frequently from BPSD than men; in the 3 months after treatment switch, moderate-AD patients showed a decrease in delusions, anxiety, and irritability, with no significant differences between genders. Ad hoc studies to investigate this potential gender effect in AD could be well worthwhile. [ABSTRACT FROM AUTHOR]

ABSTRACTBackground:Behavioral and psychological symptoms of dementia (BPSD) are a primary manifestation of brain dysfunction in dementia and a great challenge in caregiving. While BPSD are historically associated with caregiver distress, it is unclear whether there is an identifiable point where BPSD number is associated with heightened caregiver distress. The purpose of this study was to determine if such a tipping point exists to assist clinicians in identifying caregiver compromise.Methods: Analyses were performed with three datasets totaling 569 community-dwelling persons with dementia and their caregivers. Each included identical demographic, BPSD, cognitive, and caregiver well-being measures. Linear regression was performed with 16 BPSD symptoms on caregiver well-being measures and predictive values determined with receiver operating characteristic (ROC) curves and pre-defined scores for clinically significant distress.Results: Of the 569 persons with dementia, 549 (96%) displayed at least one BPSD, mean of 5.7 (SD = 3.06) symptoms in the past month. After controlling for covariates, BPSD symptom number was significantly associated with caregiver depression and burden (p < 0.01 for both models). Findings indicate ≥ 4 BPSD has strong predictive values for depression (sensitivity 85%, specificity 44%, area under ROC curve 0.62, p < 0.01), and burden (sensitivity 84%, specificity 43%, area under ROC curve 0.67, p < 0.01).Conclusions: Caring for persons with four or more BPSD appears to reflect a tipping point for clinically meaningful distress. Findings have implications for clinicians working with persons with dementia and their caregivers and suggest need for continuous monitoring of BPSD and identification of at risk caregivers. [ABSTRACT FROM AUTHOR]

Background and aims: Caregivers of individuals with neurodegenerative diseases, including frontotemporal dementia (FTD), Lewy body dementia (DLB), and Alzheimer's disease (AD), experience high levels of psychological and physical stress, likely due to behavioral and psychological symptoms of dementia (BPSD). This study is the first to simultaneously evaluate the effects of BPSD on caregiver burden in these three types of dementia. Method: A total of 214 dementia patients, including probable FTD (n = 82), DLB (n = 22), and AD (n = 110), as well as their primary caregivers, were assessed using psychological inventories and cognitive evaluation. The FTD group was further divided into the three established clinical variants: behavioral variant frontotemporal dementia (bvFTD, n = 51), non-fluent variant primary progressive aphasia (nfvPPA, n = 15), and semantic variant primary progressive aphasia (svPPA, n = 16). Cognitive impairment and neuropsychiatric symptoms were assessed using the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test, and Neuropsychiatric Inventory (NPI), respectively. Caregiver burden was assessed using the Zarit Burden Inventory (ZBI). Results: FTD patients had higher NPI and ZBI scores than DLB and AD patients, whose scores were similar. Logistic regression analysis revealed that the factors influencing caregiver burden for each group were: FTD: total NPI scores, agitation, and aberrant motor behavior; bvFTD: total NPI scores; DLB: total NPI scores; and AD: total NPI scores, onset age, apathy, and ADL. Caregivers of bvFTD patients had the highest levels of burden, which were significantly greater than for caregivers of nfvPPA, svPPA, DLB, and AD patients. Conclusion: BPSD was highly correlated with emotional burden in caregivers of FTD, DLB, and AD patients. The highest burden was observed in bvFTD caregivers. [ABSTRACT FROM AUTHOR]

Behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer’s disease have a strong correlation with cognitive impairment and impairment in activities of daily living. Although recent studies have reported that gender may play a role in BPSD, this finding was not evident in several other studies. The present study classified patients with Alzheimer’s disease into groups with mild and moderate dementia to examine the gender differences in BPSD in each group. We divided a total of 125 patients diagnosed with Alzheimer’s disease according to the criteria of the fifth edition of the Diagnostic and Statistic Manual of Mental Disorders (DSM-5) into groups with mild and moderate dementia. Then we examined whether the groups showed differences in memory functions, activities of daily living, and BPSD depending on gender. Our results showed a significant gender difference in Depression/Dysphoria symptoms (BPSD) among the patients in the mild dementia group ( t = −2.344, p < 0.05), but there was no significant gender difference among the patients in the moderate dementia group. For both the mild and moderate dementia groups, there were no significant gender differences in memory functions and activities of daily living. The results of this study indicated that female patients with mild dementia are more vulnerable to depression than male patients. Future studies should more continuously examine a variety of factors that affect BPSD depending on the severity of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Purpose: Homocysteine has been associated with cognitive impairment and various psychiatric symptoms. This study was designed to clarify whether a relationship exists between the serum levels of homocysteine and the behavioral and psychological symptoms of dementia. Methods: Patients with Alzheimer's disease (n=77) and control subjects (n=37) were included in this study. History taking, physical examination, and cognitive assessment were carried out as part of the investigation for the diagnosis of Alzheimer's disease based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The Mini-Mental State Examination, Global Deterioration Scale, Clinical Dementia Rating, and the Korean version of the Neuropsychiatric Inventory were applied to all patients. The patients' serum homocysteine, folate, and vitamin B12 levels were measured. Results: Patients with Alzheimer's disease had statistically significantly lower Mini-Mental State Examination scores and higher serum homocysteine levels compared to the control subjects. Mean serum folate and vitamin B12 concentration were significantly lower in patients with Alzheimer's disease compared to control subjects. A statistically significant positive correlation was found between the serum homocysteine levels and the Neuropsychiatric Inventory subdomains, including delusion, agitation/aggression, depression/dysphoria, elation/euphoria, apathy/ indifference, and disinhibition. No statistically significant correlation was found between the serum homocysteine concentration and the Mini-Mental State Examination, Global Deterioration Scale, or Clinical Dementia Rating. Conclusion: Associations between the serum homocysteine levels and behavioral and psychological symptoms of dementia were observed, raising the possibility of an etiological role. However, the correlations between the folate or vitamin B12 levels and the Neuropsychiatric Inventory scores were not significant. The pathophysiological mechanisms underlying these findings remain to be elucidated. This was a cross-sectional study and the findings should be confirmed by repetitive, prospective longitudinal studies in a larger group of patients with neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rivastigmine ameliorates depressive-like behaviors in olfactory bulbectomized mice. [•] 5-HT1A receptor is involved in rivastigmine-induced anti-depressive effects. [•] Rivastigmine-induced neurogenesis is partially mediated by 5-HT1A receptor. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To study the association between cerebral white matter disease and burden of behavioral and psychological symptoms (BPSD) among patients with moderate to severe AD. Methods: Patients with moderate to severe AD having undergone MRI brain, cognitive and behavioral evaluations were studied. BPSD was diagnosed based on established clinical guidelines. White matter hyperintensity (WMH) and medial temporal lobe atrophy (MTA) were quantified by a blinded rater. Results: 122 AD patients were studied. Age [76.84 vs. 72.70, p=0.014] and MMSE [11.69 vs. 15.16, p<0.001] was significantly higher in patients with BPSD. BPSD patients demonstrated higher periventricular [5.44 vs. 4.21, p<0.001], deep subcortical [5.07 vs. 3.43, p<0.001], and total WMH [10.51 vs. 7.65, p<0.001] compared to non-BPSD patients. Higher proportion of BPSD patients had WMH in the highest tertile of severity (82.22% vs. 45.45%, p<0.001). After correcting for age, baseline cognition and degree of MTA, total WMH remained significantly associated with a diagnosis of BPSD [odds ratio: 1.45 (1.14–1.85; p=0.002)]. With severe WMH, the association is significantly increased [odds ratio: 4.3 (1.3–12.5); p=0.016]. Conclusion: WMH is independently associated with BPSD in moderate to severe AD. Optimizing vascular risk factors may be a strategy to reduce the severity of BPSD in AD. [Copyright &y& Elsevier]

Background:Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses.Methods:MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale – Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6–DS baseline)) – (placebo (DS week 6–DS baseline)).Results:In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06–1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09–1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment.Conclusion:These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population. [ABSTRACT FROM AUTHOR]

Abstract: Based on evidence of an increased risk of death, drug agencies issued safety warnings about the use of second generation antipsychotics (SGAs) in the elderly with dementia. The French agency issued a warning in 2004. which was extended to all antipsychotics in 2008. Little is known about the impact of these warnings on use. We conducted a quasi-experimental study (interrupted time-series) in France, for 2003–2011, including subjects aged ≥65 with dementia and subjects aged ≥65 without dementia in the EGB database (1/97th representative random sample of claims from the main Health Insurance scheme). Outcomes were monthly rates of use of antipsychotics (by class and agent) and of five comparison drug classes (antidepressants, benzodiazepines, dermatologicals, antidiabetics, antiasthmatics). Trends were analyzed by joinpoint regression, impact of warnings by linear segmented regression. In patients with dementia (n=7169), there was a 40% reduction in antipsychotic use from 14.2% in 2003 to 10.2% in 2011. The reduction began before 2004 and was unaffected by the warnings. Use of first generation antipsychotics declined over the period, while use of SGAs increased and leveled off from 2007. Use of the five comparison drug classes increased on the period. In subjects without dementia (n=91,942), rates of overall antipsychotic use decreased from 2.3% in 2003 to 1.8% in 2011 with no effect of the warnings. Meanwhile, use of SGAs continuously increased from 0.37% to 0.64%. Antipsychotic use decreased in the elderly between 2003 and 2011, especially in dementia. The timing of the decrease, however, did not coincide with safety warnings. [Copyright &y& Elsevier]

Behavioral and psychological symptoms of dementia (BPSD) are commonly observed over the course of Alzheimer's disease (AD). However, it is unclear whether BPSD are part of AD neuropathology or rather represent a psychological reaction to cognitive disabilities. Using voxel-based-morphometry (VBM), we aimed to clarify this issue by investigating patients with AD at different clinical stages. Twenty-seven patients with AD (12 early [ADe] and 15 moderate [ADm]), 19 with amnestic mild cognitive impairment (a-MCI), and 23 healthy controls underwent MRI scanning at 3T. Assessment of BPSD was done in each patient using the Neuropsychiatric Inventory-12 (NPI-12). VBM was used to investigate changes in grey matter (GM) atrophy across groups, and associations between regional GM volumes and occurrence and severity of BPSD in patients. Mood disorders, anxiety, and agitation were present in both a-MCI and AD, while psychotic symptoms were observed mainly in AD. As expected, VBM showed only limited areas of GM atrophy in a-MCI patients, with a progressive extension in ADe and ADm patients (PFWE-corrected-values < 0.05). Disinhibition was strongly associated with GM volume in bilateral cingulate and right middle frontal gyri, while delusions were associated with GM volume in right hippocampus (PFWE-corrected-values < 0.05). This study confirms that BPSD are present since the earliest AD stages. Interesting associations were found in regions traditionally implicated by AD neuropathology. This suggests that BPSD are likely to represent clinical features of AD and should be regarded for their diagnostic and prognostic value. [ABSTRACT FROM AUTHOR]

Abstract: Yokukansan (YKS) is used frequently against behavioral and psychological symptoms of dementia (BPSD) together with donepezil in patients with Alzheimer''s disease (AD). Here, we investigated the efficacy and safety of YKS in patients with AD in a non-blinded, randomized, parallel-group comparison study. Patients who had at least one symptom score of four or more on the Neuropsychiatric Inventory (NPI) subscales were enrolled in the study. The subjects were randomly assigned to the YKS-treated group (YKS/donepezil combination therapy group) and the non-YKS-treated group (donepezil monotherapy group). TSUMURA Yokukansan (TJ-54, 7.5g, t.i.d.) was administered in a four-week study treatment period. The subjects were evaluated twice at the start (Week 0) and completion (Week 4) of the study treatment in terms of NPI, Mini-Mental Status Examination (MMSE), Disability Assessment for Dementia (DAD), Zarit Burden Interview, and Self-rating Depression Scale (SDS). The efficacy analysis was performed in 29 patients (YKS-treated group) and 32 patients (non-YKS-treated group). The NPI total score improved significantly more in the YKS-treated group than in the non-YKS-treated group. In the NPI subscales of agitation/aggression and irritability/lability, the YKS-treated group showed significantly greater improvement than the non-YKS-treated group, but no statistically significant improvement was seen with YKS in the other subscales. There were no significant differences between the YKS-treated group and the non-YKS-treated group in MMSE, DAD, Zarit Burden Interview and SDS. No adverse reactions were noted in either group. The results of this study showed that YKS is safe and effective in the treatment of BPSD in AD patients. [Copyright &y& Elsevier]

Background: To evaluate the impact of donepezil hydrochloride on the care burden on family members of patients with Alzheimer's disease (AD). At present, donepezil is the only drug approved for the treatment of AD in Japan. Although the care burden on primary caregivers of AD patients comprises both physical and psychological burdens and donepezil is recognized to improve cognitive dysfunction and associated symptoms, there are few data on the effects of the drug on the care burden. Methods: Of the uninstitutionalized AD patients who visited a dementia clinic between June 2008 and May 2009 with their primary family caregivers, 416 subjects who satisfied the enrollment criteria were registered for the study. All participants provided informed consent. Assessment included changes in scores on the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI) and the Mini-Mental State Examination (MMSE), as well as the presence of behavioral and psychological symptoms of dementia (BPSD). Caregivers answered the questionnaires at baseline and after 12 weeks treatment with donepezil (starting dose 3 mg, p.o., once daily, followed by 5 mg after 1 or 2 weeks). Results: There were significant changes in mean scores on the J-ZBI (−1.9 ± 9.5; P < 0.01) and MMSE (+0.9 ± 2.9; P < 0.01) from baseline to Week 12, without significant correlation between these two scores. In patients with BPSD, there was a significant decrease in J-ZBI scores over the 12 weeks ( P = 0.013); in contrast, in patients without BPSD, the decrease in the J-ZBI score did not reach statistical significance ( P = 0.418). Conclusions: The results indicate that donepezil improves cognitive function and some of the BPSD. As a possible consequence of improvements in BPSD, donepezil may also reduce caregivers' burden. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and often accompanied during its progression by behavioral and psychological symptoms of dementia (BPSD). We decided to evaluate the association between AD-related behavioral disturbances and the short/long (S/L) polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). This functional polymorphism modulates SLC6A4 transcription rate, with the S-allele having a 2-fold reduced efficiency, leading to a diminished availability of 5-HT that might in turn trigger behavioral and cognitive alterations. The SLC6A4 promoter functional single nucleotide polymorphism rs25531 (A→G) was genotyped as well. We collected 235 sporadic AD subjects that were classified as AD with (n = 122) or without (n = 113) behavioral alterations, assessed with the Spontaneous Behavior Interview scale, section Behavioral Problems (SBI-BP). Comparing the genotypic and allelic frequencies of AD without and with BPSD, we did not find a difference for the 5-HTTLPR or the rs25531, even after stratification according to single SBI-BP item. We conclude that 5-HTTLPR and rs25531 are not major genetic modulators of BPSD development in AD. [ABSTRACT FROM AUTHOR]

Dopamine D3 receptor (DRD3) is present in the limbic system, which is thought to regulate affect, cognition, and activity. Thus a functional change in the DRD3 gene could in turn affect the cognitive and psychiatric symptoms of dementia of Alzheimer's type (DAT). We investigated a possible association of DRD3 genotype with DAT and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for DRD3 and apolipoprotein E (ApoE) was determined using restriction fragment length polymorphism in 210 patients with mild DAT and 224 age- and sex-matched non-demented controls. The occurrence of BPSD during the course of mild dementia was demonstrated using the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). No significant differences in DRD3 genotype were identified between DAT and controls, regardless of ApoE ℇ4. Among the DAT with BPSD, however, a significant association was observed between the presence of the DRD3 glycine allele and paranoid and delusional ideation, regardless of ApoE ℇ4. In conclusion, DRD3 gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of paranoid and delusional ideation during the course of mild DAT. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to evaluate the relationship between aging and the behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease (AD). Methods: Eligible subjects were consecutively referred AD patients with BPSD. According to patient age at the time of the test, the AD patient group ( n = 79, whole AD group (WADG)) was divided into two groups: a relative older group (OG) in the whole AD group (WAD) (age at the time of test was 81 years or more, n = 40) and a relative younger group (YG) in the WAD (age at the time of test was below 81 years, n = 39). A comparison was made of the demographic data (sex difference, educational level and severity of dementia), cognitive functions and BPSD between the groups. BPSD was evaluated using the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). The factor analysis of BPSD was conducted in the WADG as well as in the OG and YG. Results: Sex difference, educational level, severity of dementia and cognitive functions were not different; however, the total score of the BEHAVE-AD symptom domain in diurnal rhythm was significantly higher in the OG than in the YG (Student's t-test: P < 0.05). Factor analysis showed that psychosis was the first factor in the OG, but was the third factor in the YG and that the psychotic symptoms were caused by anxieties and phobias in the OG. Conclusion: From these results, we found that the effects of aging on the BPSD in AD were characterized by diurnal rhythm disturbance and psychosis. [ABSTRACT FROM AUTHOR]

Background: Donepezil is effective in maintaining cognitive function in patients with mild to moderate Alzheimer's disease (AD). However, not all patients respond to donepezil. In the present study, we examined the short- and long-term effects of donepezil on cognitive function after 2 years treatment. Methods: The present retrospective study was performed on 122 AD outpatients who had been taking donepezil for ≥1 year. All subjects underwent periodic examination of cognitive function (Mini-Mental State Examination (MMSE), Rorschach Cognitive Index (RCI)) and clinical evaluation on the Clinical Dementia Rating (CDR); first before starting treatment and then at 4-month intervals after initiation of donepezil. Patients were divided into three groups: (i) MG, the ‘maintained’ group, in which the global CDR score was maintained during treatment; (ii) DeG, the ‘declined’ group, in which the global CDR score increased; and (iii) DrG, the drop out group, who discontinued the treatment. Changes in scores on the MMSE and RCI were compared before treatment and at 4-month intervals within each group. In addition, over each 4-month period, MMSE and RCI scores were compared between the three groups. Furthermore, to investigate the condition of effective treatment, the reasons why donepezil treatment was discontinued in the DrG were examined. Results: The most frequent reason for discontinuation was the appearance of behavioral and psychiatric symptoms of dementia (BPSD), which were more frequently observed in the DrG. Although depression and/or disinclination were more frequent in the MG, hyperactivity was more frequent in the DeG and DrG. Before treatment, patients in the DrG exhibited significantly lower scores on the MMSE than did patients in the MG and DeG. Upon examination 4 months after starting treatment, patients in the MG showed cognitive improvement on the MMSE and RCI, whereas those in the DeG showed cognitive deterioration on the MMSE. Conclusion: The results of the present study suggest that when a short-term beneficial effect of the donepezil on cognitive functions is seen, long-term effect may also be expected at 2 years. Periodic clinical evaluation and examination of cognitive function is indispensable for effective donepezil treatment. [ABSTRACT FROM AUTHOR]

Background: To investigate the efficacy and safety of donepezil hydrochloride (Aricept®; Eisai Co., Ltd, Tokyo, Japan), we conducted a post-marketing survey in Japanese patients with Alzheimer's disease (AD) who also had behavioral and psychological symptoms of dementia (BPSD), such as hallucinations/delusions, wandering, and aggression, which cause the greatest burden on caregivers. Methods: A prospective, centrally registered investigation was conducted through regular clinical settings with patients diagnosed as mild to moderate AD presenting with hallucinations/delusions, wandering, and/or aggression. The treatment period was 12 weeks and no restrictions were placed on concomitant medications. Results: The BPSD improvement rates at last-observation-carried-forward (LOCF) were 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For all symptoms, improvement rates increased with the duration of the treatment period. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Assessment of cognitive function with both the revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE) indicated significant improvements after treatment. There were significant differences in the changes in HDS-R scores between patients whose hallucinations/delusions or wandering were improved and patients whose symptoms were not improved. Moreover, the data suggested a possible correlation between changes in hallucinations/delusions and HDS-R scores, changes in hallucinations/delusions and MMSE scores, and changes in wandering and MMSE scores. Patients in whom BPSD improved also demonstrated a greater improvement in cognitive function compared with patients in whom no improvement in BPSD was noted. Nursing burden on caregivers at LOCF showed 3.6% for ‘No burden’, 54.1% for ‘Burden decreased’, and 4.5% for ‘Burden increased.’ There was an increase in the combined ratio of ‘No burden’ and ‘Burden decreased’ in proportion with prolonged treatment period. Patients with improved BPSD had a significantly greater ratio (88.5–94.4%) of ‘No burden’ plus ‘Burden decreased’ than those patients in whom no improvement in BPSD was noted. Conclusions: These results suggest that donepezil not only improves the cognitive dysfunction of AD patients, but may also relieve BPSD in these patients. Treatment with donepezil was also found to alleviate the burden of caregivers for approximately 60% of patients. Moreover, the results indicate that donepezil is unlikely to trigger potential risks of excessive deterioration of BPSD, which would result in a heavier burden of nursing care. [ABSTRACT FROM AUTHOR]

Background: The proportion of the population aged 85 years and older has increased rapidly in Japan, reaching 2.5 million (1.99%) in 2002. Under these circumstances, the number of dementia patients increases annually. However, few studies have focused on Alzheimer's disease (AD) with an age at onset older than 85 years (oldest old AD). The aims of the present study were to determine the prevalence of the behavioral and psychological symptoms of dementia (BPSD) in patients with oldest old AD compared with those with young old AD. Methods: Fifty-eight untreated AD patients were divided into two groups: young old AD patients (age at onset between 65 and 70 years; n = 28) and oldest old AD patients (age at onset 85 years or older; n = 30). Then, BPSD were compared between the two groups. Results: There were significant differences in the frequencies of hallucinations (χ2 = 7.43; P = 0.011) and delusional misidentification syndrome (DMS; χ2 = 7.26; P = 0.011) between the two groups. Conclusions: The results of the present study suggest that aging may play a part in the occurrence of hallucinations and DMS in oldest old AD patients. [ABSTRACT FROM AUTHOR]

Background When comparing with early-onset Alzheimer's disease (EO-AD) and late-onset Alzheimer's disease (LO-AD), some symptomatological differences in clinical features can be seen between them. Rapid progression, more severe language problems or visuospatial dysfunction occur more often in EO-AD patients. However, there have been very few reports about the differences in behavioral and psychological symptoms between these two groups. Aim The aim of this study was to demonstrate the differences in behavioral symptoms between EO-AD and LO-AD groups. Method Three hundred and seven consecutive outpatients with AD were put into an EO-AD group (46 patients) or a LO-AD group (261 patients). Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment. Results Significant differences were found between the EO-AD and LO-AD groups in terms of NPI total score (EO-AD: 10.3 ± 10.9, LO-AD: 17.8 ± 17.0, p = 0.004) and number of patients who experienced each NPI subscale score (delusion; EO-AD: 13.0%, LO-AD: 50.6%, p < 0.001). There were no differences in cognitive functions or dementia severity between two groups. Conclusion In EO-AD, behavioral and psychological symptoms are relatively fewer than LO-AD at the first medical assessment. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer''s disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4±9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses’ Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy. [Copyright &y& Elsevier]

Background: Behavioral and psychological symptoms of dementia (BPSD) increase the burden of caregiving. In 2004, the US Food and Drug Administration issued a warning on an increase in the mortality rate in elderly patients using antipsychotics. Thereafter, although the need for antipsychotics for BPSD has increased, discussions regarding their indication have continued. Methods: The present study was performed in 18 patients with Alzheimer's disease (AD) and patients with vascular dementia (VaD) who were treated with risperidone because of BPSD. Changes in the dose of risperidone and the beneficial and adverse effects of risperidone were evaluated for 3 months after the start of antipsychotic therapy. Results: The mean starting dose of risperidone was 0.62 ± 0.30 mg (62 ± 30 mg chlorpromazine (CP) equivalents), which, after 3 months, increased to 0.99 ± 0.49 mg risperidone (99 ± 49 mg CP equivalents). The symptoms of BPSD at the beginning of treatment were delusions (48% of patients) and violence (22% of patients). In the 3-month treatment period, an improvement in BSPD symptoms was recorded in 78% of patients. During the study period, adverse effects were observed in 65% of patients: 26% of patients reported falling and extrapyramidal symptoms were seen in 13%. There were no cardiovascular events or deaths. Conclusion: In the present study, low doses of risperidone were used for the treatment of BPSD and no serious side-effects were observed. An atypical antipsychotic can be one of the treatment options if a thorough risk assessment of the cardiovascular system is made and informed consent is obtained. [ABSTRACT FROM AUTHOR]

Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer's Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. Purpose. To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. Methods. AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. Results. APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, "Psychosis" and "Hyperactivity" resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and "genexgene" interactions. Conclusions. We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the "genexgene" interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms. [ABSTRACT FROM AUTHOR]

Background Alzheimer's disease (AD) is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% of patients with dementia. Although new information has emerged in recent years on the treatment of psychosis and agitation in dementia, very little information is available about the treatment of anxiety symptoms in this population. Objectives To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD. Methods A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were ≥ 2. The analysis included 120 patients. Results Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p = 0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049). Conclusions These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]