The clinical problem of neuropsychiatric signs and symptoms in dementia.
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ABSTRACT: Purpose of review
This article reviews behavioral signs and symptoms of dementia that can lead to increased mortality, excessive cognitive and functional disability, early institutionalization, and increased caregiver burnout.Recent findings
Almost all patients with a dementia will develop significant behavioral disturbances at some point over the course of their illness. These behavioral signs and symptoms rarely fit into usual diagnostic classifications or meet full criteria for a formal major psychiatric disorder.Summary
Treatment of behavioral signs and symptoms of dementia should include both pharmacologic and nonpharmacologic interventions. There are currently no treatments for these disturbances approved by the US Food and Drug Administration. Best judgment should be used in identifying dominant target symptoms and matching them to the most relevant drug class. Implementing nonpharmacologic interventions before the development of neuropsychiatric symptoms may prevent triggers related to a progressively lowered stress threshold and therefore is key in the treatment of all patients with a dementia.
SUBMITTER: Burke A
PROVIDER: S-EPMC10563909 | biostudies-literature | 2013 Apr
REPOSITORIES: biostudies-literature
Publications
The clinical problem of neuropsychiatric signs and symptoms in dementia.
Burke Anna A Hall Geri G Tariot Pierre N PN
Continuum (Minneapolis, Minn.) 20130401 2 Dementia
<h4>Purpose of review</h4>This article reviews behavioral signs and symptoms of dementia that can lead to increased mortality, excessive cognitive and functional disability, early institutionalization, and increased caregiver burnout.<h4>Recent findings</h4>Almost all patients with a dementia will develop significant behavioral disturbances at some point over the course of their illness. These behavioral signs and symptoms rarely fit into usual diagnostic classifications or meet full criteria fo ...[more]
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Project description:ObjectiveTo study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS).MethodsThis is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat.ResultsTwenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPItotal: 3.2, 95% confidence interval [CI] -3.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI -3.0 to 12.2), quality of life (Quality of Life-Alzheimer's Disease -0.5, 95% CI -2.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI -0.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n = 16; placebo, n = 14, p = 0.36). No effects on vital signs, weight, or episodic memory were observed.ConclusionsOral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally well-tolerated.Classification of evidenceThis study provides Class I evidence that for patients with dementia-related NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is well-tolerated.
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Project description:Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume.
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Project description:IntroductionNeuropsychiatric symptoms (NPSs) are common in dementia with Lewy bodies (DLB) but their neurobiological mechanisms are poorly understood.MethodsNPSs and cognition were assessed annually in participants (DLB n = 222; Alzheimer's disease [AD] n = 125) from the European DLB (E-DLB) Consortium, and plasma phosphorylated tau-181 (p-tau181) and p-tau231 concentrations were measured at baseline.ResultsHallucinations, delusions, and depression were more common in DLB than in AD and, in a subgroup with longitudinal follow-up, persistent hallucinations and NPSs were associated with lower p-tau181 and p-tau231 in DLB. In adjusted linear mixed-effects models, hallucinations at baseline were associated with greater longitudinal cognitive impairment in DLB, with a significant interaction with p-tau231.DiscussionHigher p-tau181 and p-tau231 levels were associated with a lower longitudinal risk of NPSs and hallucinations in early-stage DLB. However, the interaction between hallucinations and p-tau231 suggests that when AD co-pathology and hallucinations do co-exist in DLB that they may synergistically exacerbate cognitive decline.HighlightsNeuropsychiatric symptoms (NPSs) were more common in dementia with Lewy bodies (DLB) than in Alzheimer's disease (AD). Lower plasma phosphorylated tau-231 (p-tau231) and p-tau181 levels were associated with persistent hallucinations in DLB. Lower plasma p-tau231 and p-tau181 levels were associated with an increased risk of persistent NPSs in early DLB. Hallucinations at baseline were associated with greater cognitive dysfunction in DLB, and there was an interaction with p-tau231.
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Project description:IntroductionCirculating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia.ObjectiveThe objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms.MethodsWe measured baseline serum Trp, neopterin, pyridoxal 5'-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer's disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)-adjusted P values (Q values) are reported.ResultsKynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years (Q < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time (Q < 0.001). Post hoc, both KKR and KA were associated with more hallucinations (Q < 0.05).ConclusionsKynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.
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Project description:ObjectiveTo examine whether associations between individual neuropsychiatric symptoms (NPS) and incident Alzheimer's dementia (AD) differ in men versus women.MethodsData were acquired from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Two sets of older (≥ 60 years) participants were formed: one of cognitively unimpaired (CU) individuals, and one of participants with mild cognitive impairment (MCI). NPS were assessed using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models examined associations between individual NPS and AD incidence separately for each participant set. These models featured individual NPS, sex, NPS by sex interactions as well as a number of covariates.ResultsThe analysis involved 9,854 CU individuals followed for 5.5 ± 3.8 years and 6,369 participants with MCI followed for 3.8 ± 3.0 years. NPS were comparably associated with future AD in men and women with MCI. Regarding CU participants, the following significant sex by NPS interactions were noted: female sex moderated the risk conferred by moderate/severe apathy (HR = 7.36, 3.25-16.64) by 74%, mitigated the risk conferred by moderate/severe depression (HR = 3.61, 2.08-6.28) by 52%, and augmented the risks conferred by mild depression (HR = 1.00, 0.60-1.68) and agitation (HR = 0.81, 0.40-1.64) by 83% and 243%, respectively.ConclusionsApathy, depression and agitation were differentially associated with incident AD in CU men and women. No individual NPS was associated with different risks of future AD in men versus women with MCI.
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Project description:BackgroundNeuropsychiatric symptoms (NPS) are common in individuals with Alzheimer's disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia.MethodsLiterature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges' g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses.ResultsSixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 [95% confidence interval 0.78, 2.35]) and overall NPS severity (k = 13, g = 0.04 [- 0.04, 0.12]). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms (k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior (k = 6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24 [0.14, 0.34]), delusions (k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior (k = 9, g = 0.17 [0.08, 0.26]), while apathy was more severe among males compared to females (k = 11, g = - 0.10 [- 0.18, - 0.01]). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics.DiscussionFemale sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia.
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Project description:BackgroundNeuropsychiatric symptoms (NPS) of dementia are a common issue in dementia patients which can lead to poor medical and functional outcomes. Pharmacological interventions are its treatment of choice. However, whether to use pharmacological treatments in this population and which drug should be preferred remain controversial. We therefore aimed to compare and rank pharmacological interventions for NPS according to their efficacy and acceptability profiles by quantifying information from randomized controlled trials (RCTs).MethodsWe will include all RCTs reported as double-blind and comparing one active drug with another or with placebo that compare cholinesterase inhibitors (ChEIs), N-methyl-D-aspartic acid (NMDA) receptor modulators, antipsychotics, antidepressants, and mood stabilisers. Studies will be retrieved by searching electronic databases, including Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, Clinicaltrial.govs, EMBASE, and with no date or language restrictions. The primary outcomes were efficacy (change in overall symptoms) and acceptability (all-cause discontinuation). The network meta-analysis (NMA) will be conducted in R software within a Bayesian framework. The quality of evidence will be evaluated using the Cochrane risk of bias tool, and the GRADE approach. We will conduct subgroup analyses to assess the robustness of our findings.ResultsThe results of this study will be published in a peer-reviewed journal.ConclusionsThis systematic review will synthesize the available evidence on the comparative efficacy of different pharmacological approaches in the management of overall NPS, agitation, psychosis, apathy and depressive symptoms in dementia patients. The results of the present NMA will influence evidence-based treatment decisions for clinicians.
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Project description:BackgroundIn 2016, the global number of individuals living with dementia was 43.8 million, representing a 117% increase from 1990-mainly due to increases in aging and population growth. Up to 90% of individuals with dementia experience neuropsychiatric symptoms (NPS). However, the limitations of current treatments for NPS have drivent he search for safer pharmacotherapies-including cannabinoids.AimTo assess the efficacy and acceptability of cannabinoids for the treatment of NPS in individuals with dementia.DesignSystematic review and meta-analysis of clinical trials.Setting and participantsOf 6,902 papers, 9 were eligible (n = 205, 44% female, 78 ± 7 years, 85% Alzheimer disease). Trials were in North America and Europe and explored tetrahydrocannabinol (n = 3), dronabinol (n = 5), or nabilone (n = 1).MeasurementTitles/abstracts were independently screened by one reviewer and reviewed by a second. Full-text screening was by two reviewers with discrepancies resolved via a third reviewer. We extracted data on the standardized mean difference (SMD) for several NPS instruments, trial completion, and adverse events. Data were pooled using random-effects models.FindingsCannabinoids led to significant improvements across NPS instruments, including the Cohen Mansfield Agitation Inventory (SMD = -0.80; 95% confidence interval [CI], -1.45 to -0.16), the Neuropsychiatric Inventory (SMD = -0.61; CI, -1.07 to -0.15), and nocturnal actigraphy (SMD = -1.05; CI, -1.56 to -0.54h). Cannabinoids were well-tolerated, with an overall trial completion rate of 93% (193/205) and no serious treatment-related adverse events. Treatment efficacy was associated with baseline dementia severity and dose, but not dementia subtype, age, or sex. The overall study quality was rated as low.ConclusionsThere is preliminary evidence for the efficacy and tolerability of cannabinoids as treatments for NPS. Population-based studies are needed to characterize their real-world effectiveness and acceptability.
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