Gender Differences in Neuropsychiatric Symptoms in Mild to Moderate Alzheimer's Disease Patients Undergoing Switch of Cholinesterase Inhibitors: A Post Hoc Analysis of the EVOLUTION Study.
ABSTRACT: 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.
Project description:Background:Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan. Objective:To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD. Methods:In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm2; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm2; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24. Results:A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 (p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period. Conclusion:Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI.
Project description:AIMS:Little is known about how behavioural and psychological symptoms of dementia (BPSD) manifest in the general hospital. The aim was to examine the frequency of BPSD in general hospitals and their associations with nursing staff distress and complications in care. METHODS:Cross-sectional representative study with 1469 patients aged ?65, including 270 patients with dementia, of 33 randomly selected general hospitals in Germany. BPSD and complications were reported by nurses. RESULTS:Overall frequency of BPSD was higher in patients with dementia (76%) than without (38%). The most frequent symptoms in patients with dementia were nighttime disturbances (38%), depression (29%) and aberrant motor behaviour (28%) and the most distressing symptoms for nursing staff were delusions, aggression and nighttime disturbances. The overall frequency of BPSD increased from 67% in mild dementia, to 76% in moderate dementia and to 88% in severe dementia. The most frequent symptoms in patients without dementia were depression (19%), nighttime disturbances (13%) and irritability (13%). The most distressing symptoms were aggression and delusions, while the same symptoms were consistently rated as less distressing than in patients with dementia. Factor analysis revealed three independent groups of BPSD that explained 45% of the total variance. First, expansive symptoms (aggression, irritability, nighttime disturbances, aberrant motor behaviour and disinhibition) were frequent, distressing for nursing staff and associated with many complications. Second, psychotic symptoms (delusions and hallucinations) were infrequent, distressing and associated with some complications. Third, affective symptoms (apathy, anxiety and depression) were frequent, non-distressing and associated with few complications. The results did not change when cases with delirium were excluded from both groups. CONCLUSIONS:BPSD are common in older hospital patients with dementia and associated with considerable distress in nursing staff, as well as a wide range of special treatments needs and additional behavioural and medical complications. Management strategies are needed to improve the situation for both patients and hospital staff.
Project description:The etiology of behavioral and psychological symptoms of dementia (BPSD) is complex, including putative biological, psychological, social and environmental factors. Recent years have witnessed accumulation of data on the association between genetic factors and behavioral abnormalities in Alzheimer disease (AD). In this research paper, our aim is to evaluate the association between the APOE, CYP46, PRNP and PRND genes and the profile of neuropsychiatric symptoms in Polish subjects with AD and mild cognitive impairment (MCI). We studied 99 patients with AD and 48 subjects with MCI. The presence and profile of BPSD were evaluated at baseline and prospectively with the Neuropsychiatric Inventory (NPI). Patients were dichotomized into those having ever experienced a particular symptom and those who did not over the whole disease period. Genotyping was performed using previously described standard protocols. The prevalence of comorbid behavioral symptoms and the overall level of behavioral burden were significantly greater in AD compared with the MCI group. In AD patients, carrier status of the T allele of the 3'UTR (untranslated region) PRND polymorphism was associated with an increased cumulative behavioral load and an elevated risk for delusions, anxiety, agitation/aggression, apathy and irritability/emotional ability. Among MCI subjects, APOE ?4 carriers demonstrated a reduced risk for nighttime behavior change. No other statistically significant genotype-phenotype correlations were observed, including the APOE, CYP46 and PRNP genes. A precise estimation of the exact significance of particular polymorphisms in BPSD etiology requires future studies on large populations.
Project description:Background:In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. Methods:This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver's stress burden were analyzed. Results:A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients' gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12-1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66-7.64) and sleep disorder (OR 1.69, CI 1.25-2.29), FTD with wandering (OR 1.62, CI 1.12-2.35), and change of appetite (OR 1.52, CI 1.03-2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients' neuropsychiatric burden (p<0.0001). Conclusion:Quarantine induces a rapid increase of BPSD in approximately 60% of patients and stress-related symptoms in two-thirds of caregivers. Health services need to plan a post-pandemic strategy in order to address these emerging needs.
Project description: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.
Project description:To discuss the pharmacology, mechanism of action, and chemical properties of the cholinesterase inhibitor (ChEI) rivastigmine; to provide a rationale for transdermal delivery and supportive clinical data, along with practical guidance on rivastigmine patch use in Alzheimer's disease and Parkinson's disease dementia.Pivotal studies of rivastigmine capsules and patch were identified using PubMed and the rivastigmine US prescribing information. PubMed searches were performed in 2013 using rivastigmine as a keyword.English-language articles related to rivastigmine considered of relevance to primary care physicians were included.Pharmacologic differences exist between rivastigmine and ChEIs. Clinical studies demonstrate symptomatic efficacy of oral rivastigmine across all stages of Alzheimer's disease and mild-to-moderate Parkinson's disease dementia. However, gastrointestinal adverse events limit access to optimal therapeutic doses. Strategies that lower maximum plasma concentrations (Cmax) and prolong time to Cmax, ie, transdermal delivery, may improve tolerability. Clinical registration studies have demonstrated improved tolerability of rivastigmine 9.5-mg/24-h patch versus 6-mg twice-daily capsules in mild-to-moderate Alzheimer's disease, and a positive benefit-risk profile of 13.3-mg/24-h versus 9.5-mg/24-h patch in patients needing enhanced efficacy. Clinical data comparing 13.3-mg/24-h versus 4.6-mg/24-h patch in severe Alzheimer's disease demonstrated efficacy on cognition and activities of daily living. These data led to approval of rivastigmine patch in severe Alzheimer's disease. Transdermal delivery also has practical advantages, including simple, once-daily administration and a visual indicator of compliance. Potential application site reactions can be minimized and need not be a barrier to treatment.In addition to practical advantages, rivastigmine patch may improve clinical outcomes throughout the course of Alzheimer's disease by providing access to high-dose efficacy without compromising tolerability.
Project description:A wide range of behavioural and psychological symptoms (BPSD) are common in dementia, and it has been suggested that groups of correlated symptoms should be studied together. Here, we describe the groups of BPSD that have been identified in the literature and how they have been used to study associations, burden, treatment and underlying biology.The literature database PubMed was searched for articles that identified clusters or factors of BPSD or used previously defined symptom groups.Sixty-two studies were included. Generally, the following symptom groups were suggested: affective symptoms, including depression and anxiety; psychosis, including delusions and hallucinations; hyperactivity, including irritability and aggression; and euphoria. Symptoms that did not show consistent results include apathy, eating disturbances, night-time behaviour disturbances, disinhibition and aberrant motor behaviour. Symptom groups differed in their associations, treatment and biology.Studies investigating symptom groups show relatively consistent results. Studying symptom groups allows similar symptoms to be studied together, which might strengthen results and may point to differences in their aetiology and treatment. However, a large amount of the individual variability of the symptoms could not be explained by the factors, and authors should carefully address their research question and hypotheses to decide if symptoms should be studied in groups or individually. Clinicians need to consider each symptom in its own right and also to be aware of the interrelations between them when assessing patients and developing strategies for treatment.
Project description:BACKGROUND: CHRNA7 encodes the ?7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. METHODS: Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ? 2 between baseline and 6 months after ChEI treatment. RESULTS: AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47-8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38-8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. CONCLUSION: For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.
Project description:Introduction:Identifying Alzheimer's disease (AD) pharmacologic treatment options that effectively reduce the risk of mortality and hospitalization in real-world settings is critical. Methods:We compared donepezil, galantamine, memantine, oral rivastigmine, and transdermal rivastigmine with regard to all-cause mortality and all-cause hospitalization risk among fee-for-service Medicare beneficiaries with AD (aged ? 65 years) using a retrospective cohort study design. Our primary analysis was based on intention to treat (ITT), but we also present as-treated analysis. Results:In our final study sample (N = 21,558), significant difference in survival among index AD medication groups were observed with donepezil being associated with better survival than memantine, and oral and transdermal forms of rivastigmine for both ITT and as-treated analysis. Difference in hazards of all-cause hospitalization among index AD medication groups was observed in ITT analysis but not in as-treated analysis. Discussion:Significant differences exist in terms of mortality and hospitalization risk with different AD medication initiation in real-world setting.
Project description:Objective::To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods::Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results::Considering 201 patients, only APOE-?4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion::Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.