Article
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Neuropsychiatric symptoms (NPS) are core features of Alzheimer's disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer's Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer's disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by the loss of function of neurons and their consequent death [1]. Although AD is not a natural consequence of aging, it is generally seen in the elderly population [2]. The main symptoms encountered in Alzheimer's disease and Alzheimer's-related dementia are called neuropsychiatric symptoms (NPS) [2]. ...
... Although AD is not a natural consequence of aging, it is generally seen in the elderly population [2]. The main symptoms encountered in Alzheimer's disease and Alzheimer's-related dementia are called neuropsychiatric symptoms (NPS) [2]. Although depression takes the first place, schizophreniform or paranoid psychosis is one of the other most common types of these symptoms [3]. ...
... Although depression takes the first place, schizophreniform or paranoid psychosis is one of the other most common types of these symptoms [3]. Describing overt syndromes in patients can become quite complex, as these NPSs may overlap into clusters of symptoms [2]. However, some of the AD syndromes have been found to be quite consistent in AD in systematic studies performed on various populations [4,5]. ...
Article
Full-text available
Neurodegenerative diseases occur due to progressive and sometimes irreversible loss of function and death of nerve cells. A great deal of effort is being made to understand the pathogenesis of neurodegenerative diseases. In particular, the prevalence of Alzheimer's disease (AD) is quite high, and only symptomatic therapy is available due to the absence of radical treatment. The aim of this review is to try to elucidate the general pathogenesis of AD, to provide information about the limit points of symptomatic treatment approaches, and to emphasize the potential neurologic effects of phytocompounds as new tools as therapeutic agents for disease prevention, retardation, and therapy. This survey also covers the notable properties of herbal compounds such as their effects on the inhibition of an enzyme called acetylcholinesterase, which has significant value in the treatment of AD. It has been proven that phytopharmaceuticals have long-term effects that could protect nervous system health, eliminate inflammatory responses, improve cognitive damage, provide anti-aging effects in the natural aging process, and alleviate dementia sequelae. Herbal-based therapeutic agents can afford many advantages and can be used as potentially as new-generation therapeutics or complementary agents with high compliance, fewer adverse effects, and lower cost in comparison to the traditional pharmaceutical agents in the fight against AD.
... Alzheimer's disease (AD) is a neurodegenerative disease characterized by a gradual decline in cognition and functional abilities. 1 In addition, neuropsychiatric symptoms (NPS) are increasingly seen as a third hallmark of AD, 9,81 as nearly all patients with AD develop NPS at some stage during the disease. e.g. 2 To improve the recognition of NPS in AD, consensus criteria have been developed for apathy, 193 psychosis, 186 and depression in AD. 29 Furthermore, the concept of mild behavioral impairment (MBI) has recently been described to enhance awareness concerning NPS as an early manifestation of AD and other types of dementia. ...
... Although the notable behavioral symptoms observed in this case are not observed in every patient with AD, NPS such as social withdrawal, apathy, and depression are very prevalent in early-stage AD, with prevalence estimates of nearly 80% in MCI and 90% in mild AD. 9,10,210 This raises the question whether a subgroup of patients diagnosed with a late-onset psychiatric disorder could actually have underlying AD. Prior studies have supported this notion, showing overrepresented AD pathology in elderly who committed suicide, with only a small portion of the sample clinically being diagnosed with dementia. ...
... Neuropsychiatric symptoms (NPS) include a wide range of symptoms including apathy, agitation, affective disturbances, and psychotic symptoms. 9 NPS are prevalent among individuals with early Alzheimer's disease (AD) dementia, 10,147 and put a large burden on people living with AD dementia and their caregivers. 40,50 Furthermore, the presence of NPS in early stage AD dementia is related to a faster cognitive decline and earlier institutionalization. 47,53 International guidelines recommend non-pharmacological interventions as first-line treatment for NPS in dementia. ...
Thesis
Full-text available
This PhD thesis investigates 1) the prevalence and course of neuropsychiatric symptoms in the early clinical stages of Alzheimer’s disease, 2) the way neuropsychiatric symptoms are currently diagnosed and treated in individuals with Alzheimer’s disease at the memory clinic, and (3) how the timely recognition and non-pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease could be improved in the memory clinic setting. With this thesis, I provided further evidence that Alzheimer’s disease entails more than deficits in memory functioning as neuropsychiatric symptoms should be considered one of the core features of early Alzheimer’s disease as well.
... Late-onset Alzheimer's Disease (LOAD) is a heterogeneous disease with comorbid clinical symptoms. Most pronounced are the neuropsychiatric symptoms (NPS) including depression that show high prevalence among LOAD patients [1][2][3][4][5][6][7]. In addition, it was demonstrated that LOAD biomarkers, such as cerebrospinal fluid (CSF) Aβ 42 and CSF total and phosphorylated tau, are associated with depression trajectories in LOAD [8]. ...
... LOAD is characterized by multiple clinical symptoms [35][36][37][38], with NPS, including depression, showing high prevalence [1][2][3][4][5][6][7]. Prior work has explored the common genetics underlying MDD and LOAD, using genetics to predict those at greater risk of developing depression [9,10]. ...
Article
Full-text available
Depression is common among late-onset Alzheimer’s Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied. Using transcriptomic and DNA-methylomic datasets from the ROSMAP cohorts, we investigated differential gene expression and DNA-methylation in LOAD patients with and without comorbid depression. Differential expression analysis did not reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex-stratification, we identified 25 differential expressed genes (DEG) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Additionally, testing differences in DNA-methylation found significant hypomethylation of CpG (cg20442550) on chromosome 17 (log2FC = −0.500, p = 0.004). Sex-stratified differential DNA-methylation analysis did not identify any significant CpG probes. Integrating the transcriptomic and DNA-methylomic datasets did not discover relationships underlying the comorbidity of depression and LOAD. Overall, our study is the first multi-omics genome-wide exploration of the role of gene expression and epigenome alterations in the risk of comorbid depression in LOAD patients. Furthermore, we discovered sex-specific differences in gene expression underlying the risk of depression symptoms in LOAD.
... They are associated with more severe outcomes such as rapid cognitive decline, more frequent hospitalizations, and earlier death (Dietlin et al., 2019;Peters et al., 2015;Spiegl et al., 2021). NPS can precede mild cognitive impairment (MCI) and dementia, in particular Alzheimer's disease (AD) (Ismail et al., 2016;Lyketsos et al., 2011). ...
... Out of the assessed 420 plasma proteins, the levels of 15 proteins significantly differed between the participants with NPS and those without. and functional decline (Ismail et al., 2016;Lyketsos et al., 2011), and suggests that the related pathological alterations may be early detected in blood plasma and serve as prognostic biomarkers. ...
Article
Neuropsychiatric symptoms (NPS) severely affect patients and their caregivers, and are associated with worse long‐term outcomes. This study tested the hypothesis that altered protein levels in blood plasma could serve as biomarkers of NPS; and that altered protein levels are associated with persisting NPS and cognitive decline over time. We performed a cross‐sectional and longitudinal study in older subjects with cognitive impairment and cognitively unimpaired in a memory clinic setting. NPS were recorded through the Neuropsychiatric Inventory Questionnaire (NPI‐Q) while cognitive and functional impairment was assessed using the clinical dementia rating sum of boxes (CDR‐SoB) score at baseline and follow‐up visits. Shotgun proteomic analysis based on liquid chromatography‐mass spectrometry was conducted in blood plasma samples, identifying 420 proteins. The presence of Alzheimer's Disease (AD) pathology was determined by cerebrospinal fluid biomarkers. Eighty‐five subjects with a mean age of 70 (± 7.4) years, 62% female and 54% with mild cognitive impairment or mild dementia were included. We found 15 plasma proteins with altered baseline levels in participants with NPS (NPI‐Q score > 0). Adding those 15 proteins to a reference model based on clinical data (age, CDR‐SoB) significantly improved the prediction of NPS (from receiver operating characteristic area under the curve (AUC) 0.75 to AUC 0.91, p = 0.004) with a specificity of 89% and a sensitivity of 74%. The identified proteins additionally predicted both persisting NPS and cognitive decline at follow‐up visits. The observed associations were independent of the presence of AD pathology. Using proteomics, we identified a panel of specific blood proteins associated with current and future NPS, and related cognitive decline in older people. These findings show the potential of untargeted proteomics to identify blood‐based biomarkers of pathological alterations relevant for NPS and related clinical disease progression.
... NPS have been observed in 60% to 98% of patients, especially in later dementia stages [8]. Remarkably, NPS in AD (NPS-AD) are highly prevalent and most patients exhibit one or multiple symptoms during the course of the disease that may range from mild to severe [9], especially depressed mood. Understanding brain-behavior relationship in terms of damaged neural circuits involvement may also help specialists to better target NPS-AD. ...
... Understanding brain-behavior relationship in terms of damaged neural circuits involvement may also help specialists to better target NPS-AD. In fact, specific brain regions (i.e., anterior cingulate and insula, amygdala, and frontal cortex), and neurotransmitter systems, particularly serotoninergic and dopaminergic mechanisms, have been proposed as factors underlying NPS-AD by sectorial neurobiological studies [9]. ...
Article
Full-text available
Background: Patients with Alzheimer's disease (AD) present with cognitive function deterioration, neuropsychiatric symptoms (NPS)-especially depression-and low quality of life (QoL). Management of AD remains difficult, especially in the elderly. Reminiscence therapy (RT) is a well-known cognitive rehabilitation intervention that can be adopted in nursing and residential care homes to restore autobiographical memory, ameliorate NPS, and improve the QoL of people with dementia. However, the evidence-based efficacy of RT for elderly patients with AD remains to be determined. Methods: Here, we synthesized findings of randomized controlled trials (RCTs) exploring the effects of RT on cognition, depression, and QoL in elderly people with AD, according to the most recent PRISMA statement. We searched for RCTs in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials, and in trial registries (i.e., clinicaltrials.gov and International Clinical Trials Registry Platform of the World Health Organization). Two review authors extracted data of interest, with cognition, depression, and QoL measures as outcomes. Results: A total of five articles were included in the final analysis. Findings globally showed that RT, both administered in individual or group sessions at least once a week for 30-35 min over a period of 12 weeks, is effective in supporting global cognition, ameliorating depression, and improving specific aspects of the QoL in elderly people with AD. Conclusions: RT has the potential to be a routine non-pharmacological therapy for elderly people with AD, thanks to its wider effects on the individual in terms of cognitive vitality and emotional status promotion, with positive implications for patient's daily life. Despite such evidences, caution should be used in findings' generalizability in relation to the paucity of existing RCTs with long-term follow-up.
... Each year approximately 10 million new cases are registered, and it is forecast that there will be 78 million cases in 2030 and 139 million in 2050, with Alzheimer's disease (AD) being the most common form of dementia, with 60-70% of cases [4]. Although AD is primarily a neurocognitive disorder, it also entails different neuropsychiatric symptoms (NPS), including apathy, depression, anxiety, agitation, aggression, and psychosis [5]. Much research has focused on symptoms such as depression [6,7], apathy [8,9], or agitation [10,11], but the relation between anxiety and AD has received much less attention. ...
Article
Full-text available
1) Background: Although cognitive impairment is considered the core deficit of dementia, anxiety disorders also have a negative influence on the social and daily life of the affected population. We have explored the exposure of relaxing scenarios in immersive Virtual Reality (iVR) as an intervention strategy for people with moderate Alzheimer's disease. (2) Methods: Three participants were recruited from a day center to participate in a five-week study, which included a Pre-and Post-evaluation with the Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory-Questionnaire (NPI-Q), Clinical Dementia Rating Scale (CDR), Global Deterioration Scale (GDS), Hamilton Anxiety Rating Scale (HARS), State-Trait Anxiety Inventory (STAI), and the anxiety subdomain of the Neuropsychiatric Inventory (NPI). Participants' heart rate, oxygen saturation, arterial pressure, and respiratory rate were also monitored during intervention sessions. Three virtual scenarios from Nature Treks VR were used as the intervention over three weeks (a total of nine sessions). (3) Results: Post-intervention anxiety assessment showed a light reduction in psychological anxiety in the HARS questionnaire. A light reduction in heart rate was also observed during the exposure to iVR. (4) Discussion: The use of virtual scenarios was a satisfactory experience for all the participants. Preliminary data point to a relaxing effect of iVR scenarios and a potential reduction in psychological anxiety, but further research is required to confirm the efficacy of the intervention.
... Some of the symptoms which develop in AD are getting lost in familiar places, difficulty in concentrating and thinking, problem in multitasking, decline in the ability to make reasonable decisions, and judgments (Shetty and Bates, 2015), struggling in once-routine activities like cooking, etc. Additionally, there are some changes in personality and behavior like apathy, depression, distrust in others, aggressiveness, mood swings, social withdrawal, irritability, wandering, changes in sleeping habits, and delusions (Lyketsos et al., 2011). (Figure 1) ...
... . AD is the most common disease of aging and is usually considered a cognitive disorder. One of the most common neuropathological hallmarks of AD is the misfolding and aggregation of the β-amyloid peptides, senile plaques, or amyloid plaques, which mainly consist of small β-amyloid peptide (Aβ) (up to 42 or 43 amino acids long) [168,169]. ...
Article
Full-text available
Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical features, such as Alzheimer’s and Parkinson’s diseases. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies, and most probably, each metal has its specific pathway to trigger cell death. As a result, exposure to essential metals, such as manganese, iron, copper, zinc, and cobalt, and nonessential metals, including lead, aluminum, and cadmium, perturbs metal homeostasis at the cellular and organism levels leading to neurodegeneration. In this contribution, a comprehensive review of the molecular mechanisms by which metals affect microglia physiology and signaling properties is presented. Furthermore, studies that validate the disruption of microglia activation pathways as an essential mechanism of metal toxicity that can contribute to neurodegenerative disease are also presented and discussed.
... Validation of NPI-Q against the NPI instrument showed that the prevalence of symptoms varied by five percent, while ratings for moderate or severe symptoms differed by less than two percent [35]. Studies indicate that nearly all PLWD will develop at least one BPSD in the course of their disease progression [8,40]. Our estimated prevalence rate of BPSD is higher than the estimated prevalence of 35-85% previously reported although the majority of these studies used a different survey tool, were conducted in high-income countries, and included PLWD who had mild cognitive impairment and were institutionalized [8,9,41]. ...
Article
Full-text available
The purpose of the study was to investigate behavioral and psychological symptoms (BPSD) prevalence, severity, and distress experienced by caregivers of people living with dementia (PLWD). A cross-sectional, population-based study was conducted in a rural area in southwestern Uganda. A Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to determine the presence of BPSD as perceived by caregivers of PLWD. We carried out both descriptive and inferential data analysis. A total of 175 caregivers of PLWD were enrolled in this study. Among PLWD, 99% had presented BPSD in the past month. Hallucinations (75%) and dysphoria/depression (81%) were the two BPSD that occurred most frequently. Most participants (70%) stated that PLWD experienced hallucinations of significant severity. Aberrant motor activity was reported by 60% of the participants as the type of BPSD that caused severe distress. There was a high positive correlation (0.82) between the total severity score and total distress scores. Interventions aimed at addressing dysphoria and hallucinations may be essential for the reduction of caregiver distress. These findings point to the need for promoting early screening for BPSDs and the provision of support to caregivers.
... The differential patterns of behavioral symptoms observed between EOAD, and LOAD indicate a pattern of selective vulnerability extending to the brain's subcortical structures. Irritability, agitation, aggression, and sleep disturbances are common in AD (Lyketsos et al., 2011). Previous studies suggest that these symptoms increase in severity across the disease course for EOAD and LOAD, irrespective of the biological sex (Ehrenberg et al., 2018). ...
Article
Full-text available
Objective This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer’s disease (LOAD) and Early-onset Alzheimer’s disease (EOAD). Method Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer’s patients’ registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. Results In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175–2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221–3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799–0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834–0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627–0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462–0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424–0.660, p < 0.001] were associated with LOAD. Conclusion Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.
... Disruption of the dopaminergic system alongside the loss of the modulatory effect that the cholinergic system exerts on the former is documented in AD, including its early clinical stages Nobili et al., 2017). The cholinergic-dopaminergic systems interaction is suggested by evidence about the loss of cholinergic neurons in AD and is associated with downstream disruption of the dopaminergic neurotransmission and subsequent onset of psychiatric symptoms (Lyketsos et al., 2011;Martorana and Koch, 2014). In addition, high-doses of anticholinergic drugs particularly mAChR antagonistscan induce psychosis (Terry, Jr, 2008). ...
Article
Acetylcholinesterase inhibitors (ChEI) are the global standard of care for the symptomatic treatment of Alzheimer's disease (AD) and show significant positive effects in neurodegenerative diseases with cognitive and behavioral symptoms. Although experimental and large-scale clinical evidence indicates the potential long-term efficacy of ChEI, primary outcomes are generally heterogeneous across outpatient clinics and regional healthcare systems. Sub-optimal dosing or slow tapering, heterogeneous guidelines about the timing for therapy initiation (prodromal versus dementia stages), healthcare providers' ambivalence to treatment, lack of disease awareness, delayed medical consultation, prescription of ChEI in non-AD cognitive disorders, contribute to the negative outcomes. We present an evidence-based overview of determinants, spanning genetic, molecular, and large-scale networks, involved in the response to ChEI in patients with AD and other neurodegenerative diseases. A comprehensive understanding of cerebral and retinal cholinergic system dysfunctions along with ChEI response predictors in AD is crucial since disease-modifying therapies will frequently be prescribed in combination with ChEI. Therapeutic algorithms tailored to genetic, biological, clinical (endo)phenotypes, and disease stages will help leverage inter-drug synergy and attain optimal combined response outcomes, in line with the precision medicine model.
... En effet, des déficits exécutifs et attentionnels sont présents (pour revue voir (Perry and Hodges, 1999)), avec notamment des troubles de la flexibilité mentale, de l'inhibition des processus automatiques et/ou de la planification (Amieva et al., 2004;Collette et al., 1999;Franceschi et al., 2007). De plus, des troubles de l'humeur et des troubles comportementaux peuvent également être observés, avec par exemple des symptômes anxieux et dépressifs, de l'apathie, ou encore l'apparition d'autres symptômes psychiatriques tels que l'agitation ou des hallucinations aux stades plus tardifs de démence (Cummings et al., 1994;Geda et al., 2013;Lanctôt et al., 2017;Lyketsos et al., 2011;Zhao et al., 2016). ...
Thesis
Full-text available
Le déclin cognitif subjectif (DCS) rapporté par une personne (auto-rapporté) ou son proche (hétéro-rapporté) fait l’objet d’un intérêt croissant dans le cadre de la maladie d’Alzheimer (MA). Le double objectif de cette thèse était de contribuer à une meilleure compréhension des corrélats cognitifs et cérébraux des deux mesures de DCS dans l’ensemble du continuum clinique de la MA, et de déterminer l’impact du type de recrutement chez les patients SCD (pour Subjective Cognitive Decline). Nos résultats indiquent que l’augmentation du DCS auto-rapporté chez les patients SCD est associée à une plus forte neurodégénérescence. De plus, un plus haut niveau de DCS hétéro-rapporté chez ces patients est associé à une diminution des performances cognitives et prédit l’augmentation des dépôts amyloïdes corticaux dans les deux ans. Les patients SCD recrutés en consultation mémoire semblent plus vulnérables à la pathologie. Chez les patients MCI (pour Mild Cognitive Impairment) et déments (ou les patients avec un MMSE<27), nous montrons une inversion de la relation existant entre le DCS auto-rapporté et la neurodégénérescence. De plus, au stade MCI uniquement, le DCS hétéro-rapporté est fortement corrélé aux dépôts amyloïdes corticaux, à la neurodégénérescence dans les régions sensibles à la MA et aux déficits cognitifs objectifs. Ces résultats supportent la nécessité de prendre en compte les deux mesures de DCS chez les personnes âgées sans déficits objectifs, dans l’espoir d’établir des recommandations ciblées et de prévenir le déclin cognitif objectif. A l’inverse, une anosognosie peut apparaître dès le stade MCI. A ce stade, il semble particulièrement pertinent de prendre en compte la mesure de DCS hétéro-rapporté qui pourrait permettre d’enrichir les essais cliniques avec des patients se situant dans le continuum biologique de la MA.
... Patients with dementia often have behavioral and psy-chological symptoms (behavioral and psychological symptoms of dementia, BPSD), which include disturbed perception, thought content, mood, behavior and sleep. The common symptoms include agitation, aggression, psychosis, depression, apathy, repetitive questioning, psychosis, sleep problems, wandering, and a variety of socially inappropriate behaviors [1]. A previous study showed that around 80% of demented patients exhibit at least one BPSD from the onset of cognitive symptoms; the most frequent disturbances were apathy (36%), depression (32%), and agitation/aggression (30%) [2]. ...
Article
Objective: Moderate and severe behavioral and psychological symptoms of dementia (BPSD) often need medical treatment to improve symptoms. Agomelatine is a selective melatonergic (MT1/MT2) agonist that has normalizing effects on disturbed circadian rhythms and disrupted sleep-wake cycles. Its activity of 5HT-2C receptor antagonism is associated with lessening depression and anxiety and increasing slow-wave sleep. Based on past clinical records and current findings it suggests that agomelatine can improve BPSD for patients. This retrospective cohort study was designed to compare the BPSD before and after using agomelatine. Methods: Records of dementia cases who had ever received agomelatine treatment for BPSD in a general hospital setting during the past 2.5 years were identified and reviewed. Scores from before and after 3 months of treatment with agomelatine were collected for Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI) to compare and analyze the difference of psychological and behavioral symptoms pre- and post-agomelatine used. Results: Records of 144 cases of dementia with BPSD who had ever used agomelatine from January 2015 to June 2017 were collected. All of the 112 cases had BPRS and CGI scores, of which 75 cases had additional NPI scores. Among these 112 cases, the BPRS and CGI scores were significantly improved in all types of dementia. NPI scores indicated that the use of agomelatine alleviated obvious symptoms and decreased overall distress, especially in the depression/poor mood, anxiety, and sleep/night behavior. Conclusion: It is consistent with an effective result of agomelatine in improving BPSD.
... Cognitive function has been reported to be more prone to decline in older people with dementia (PWD) in nursing homes (NHs) than in older people living in the community [1][2][3]. Behavioral and psychological symptoms of dementia (BPSDs) have a variety of contributing factors (e.g., neurobiologically related disease factors, acute medical illness, unmet needs, pre-existing personality and psychiatric illness factors, caregiver factors, and environmental factors), and cognitive decline, a core symptom, has also been shown to be an important contributing factor [4][5][6][7]. The occurrence of BPSDs follows a vicious cycle in which cognitive decline accelerates, resulting in impaired activities of daily living (ADLs) and increased mortality [8][9][10][11][12][13]. In addition, even PWD who have the same cognitive dysfunctions may differ in the degree of specific cognitive dysfunctions, such as memory and orientation; accordingly, BPSDs and ADLs may also differ between individuals. ...
Article
Full-text available
Background Older people with dementia (PWD) in nursing homes (NHs) tend to have decreased cognitive function, which may cause behavioral and psychological symptoms of dementia (BPSDs) and hinder activities of daily living (ADLs). Therefore, taking measures against the cognitive decline of PWD in NH and, in turn, the decline of BPSDs and ADLs is crucial. The purpose of this study was to test whether a multimodal non-pharmacological intervention (MNPI) is effective in maintaining and improving global cognitive function, BPSDs, and ADLs in PWD in NHs. Methods An intervention study using a single-case AB design was conducted in three subjects in NHs. During the non-intervention phase, participants underwent follow-up assessments, and during the intervention phase, they participated in an MNPI. The ABC Dementia Scale (which concurrently assesses ADLs [“A”], BPSDs [“B”], and cognitive function [“C”]) was used for the assessment. Results One of the three patients showed improvement in dementia severity, global cognitive function, ADLs, and BPSDs. However, the other two participants showed no improvement following the MNPI, although the possibility of a maintenance effect remained. Conclusion Although there is room for improvement of the MNPI, it may be effective in maintaining and improving cognitive function, ADLs, and BPSD, in PWD in NHs. Trial registration The University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ , No. UMIN000045858, registration date: November 1, 2021).
... Extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles are the main histopathological features of AD, clinically characterized by progressive deterioration of memory and cognition and, ultimately, brain atrophy [1,2]. AD is also associated with several comorbidities, including neuropsychiatric symptoms like agitation, apathy, depression, anxiety, aggression, and sleep-and night-time disturbances, observed in more than 50% of patients [3][4][5]. ...
Article
Full-text available
Background Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for the early pathogenesis of Alzheimer’s Disease (AD). We have previously described a progressive and selective degeneration of these neurons in the Tg2576 mouse model of AD, long before amyloid-beta plaque formation. The degenerative process in DA neurons is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss. Impairments in autophagy can be the basis for accumulation of damaged mitochondria, leading to disturbance in calcium (Ca ²⁺ ) homeostasis, and to functional and structural deterioration of DA neurons. Methods In Tg2576 mice, we performed amperometric recordings of DA levels and analysis of dopaminergic fibers in the Nucleus Accumbens – a major component of the ventral striatum precociously affected in AD patients – together with retrograde tracing, to identify the most vulnerable DA neuron subpopulations in the VTA. Then, we focused on these neurons to analyze mitochondrial integrity and Apoptosis-inducing factor (AIF) localization by electron and confocal microscopy, respectively. Stereological cell count was also used to evaluate degeneration of DA neuron subpopulations containing the Ca ²⁺ -binding proteins Calbindin-D28K and Calretinin. The expression levels for these proteins were analyzed by western blot and confocal microscopy. Lastly, using electrophysiology and microfluorometry we analyzed VTA DA neuron intrinsic properties and cytosolic free Ca ²⁺ levels. Results We found a progressive degeneration of mesolimbic DA neurons projecting to the ventral striatum, located in the paranigral nucleus and parabrachial pigmented subnucleus of the VTA. At the onset of degeneration (3 months of age), the vulnerable DA neurons in the Tg2576 accumulate damaged mitochondria, while AIF translocates from the mitochondria to the nucleus. Although we describe an age-dependent loss of the DA neurons expressing Calbindin-D28K or Calretinin, we observed that the remaining cells upregulate the levels of Ca ²⁺ -binding proteins, and the free cytosolic levels of Ca ²⁺ in these neurons are significantly decreased. Coherently, TUNEL-stained Tg2576 DA neurons express lower levels of Calbindin-D28K when compared with non-apoptotic cells. Conclusion Overall, our results suggest that the overexpression of Ca ²⁺ -binding proteins in VTA DA neurons might be an attempt of cells to survive by increasing their ability to buffer free Ca ²⁺ . Exploring strategies to overexpress Ca ²⁺ -binding proteins could be fundamental to reduce neuronal suffering and improve cognitive and non-cognitive functions in AD.
... The estimated total number of dementia cases worldwide was approximately 50 million in 2020 and is expected to increase threefold by 2050 with the aging population worldwide (World Health Organization, 2021). Along with cognitive and functional decline, nearly all people living with dementia experience behavioral and psychological symptoms of dementia at a point in the illness trajectory (Lyketsos et al., 2011). This refers to distressing perceptions, thought content, mood, and behaviors, such as delusions, hallucinations, agitation, depression, anxiety, and apathy (Kales et al., 2014). ...
Article
Full-text available
Background Although behavioral and psychological symptoms of dementia are a global public health challenge, non-pharmacological interventions using information and communication technologies can be an affordable, cost-effective, and innovative solution. Objectives This study aimed to examine the effectiveness of non-pharmacological interventions using information and communication technologies on the behavioral and psychological symptoms of dementia and identify potential moderators of intervention effects. Design Systematic review and meta-analysis of randomized controlled trials. Methods A systematic literature review was conducted using PubMed, CINAHL, PsycINFO, Embase, and the Cochrane Library from May 2022. Randomized controlled trials that examined the effects of non-pharmacological interventions using information and communication technologies on the behavioral and psychological symptoms of dementia were included. A meta-analysis using a random-effects model was performed to calculate the pooled standardized mean differences between overall symptoms and each type of symptom. For moderator analyses, subgroup and meta-regression analyses were performed. Results Sixteen trials (15 articles) met the eligibility criteria. The interventions were grouped into activity engagement interventions using digital health that provided music and reminiscence therapy, physical exercise, social interaction interventions using social robots, and telehealth-based care aid interventions that provided coaching or counseling programs. Pooled evidence demonstrated that non-pharmacological interventions using information and communication technologies exerted a large effect on depression (SMD = − 1.088, 95% CI -1.983 to − 0.193, p = 0.017), a moderate effect on overall behavioral and psychological symptoms of dementia (SMD = − 0.664, 95% CI -0.990 to − 0.338, p < 0.001), and agitation (SMD = − 0.586, 95% CI -1.130 to − 0.042, p = 0.035). No effects on neuropsychiatric symptoms (SMD = − 0.251, 95% CI -0.579 to 0.077, p = 0.133), anxiety (SMD = − 0.541, 95% CI -1.270 to 0.188, p = 0.146), and apathy (SMD = − 0.830, 95% CI -1.835 to 0.176, p = 0.106) were reported. Moderator analyses identified the mean age of the participants as a potential moderator of intervention effects. Conclusions Evidence from this systematic review and meta-analysis suggests that non-pharmacological interventions, using information and communication technologies, were an applicable approach to managing behavioral and psychological symptoms among older adults with dementia, with moderate to large effect sizes. However, evidence on anxiety and apathy is inconclusive due to the limited number of existing randomized controlled trials. Future studies with subgroup analyses are warranted to conclude the most effective types of intervention using information and communication technologies for each type of symptom. Registration CRD42021258498.
... Dementia is a syndrome, with the most common type being Alzheimer's disease (Oh and Rabins, 2019). Clinically, Alzheimer's disease is mainly characterized by comprehensive dementia, including memory disorder, cognitive disorder, executive dysfunction, and personality and behavior changes, and is accompanied by mental disorder symptoms in most patients (Lyketsos et al., 2011). Although these symptoms can be temporarily relieved by detailed care and medication, there are no specific measures to prevent or cure Alzheimer's disease (Srivastava et al., 2021). ...
Article
Full-text available
Background With the increase in the aging population worldwide, Alzheimer's disease has become a rapidly increasing public health concern. Monitoring the dementia disease burden will support health development strategies by providing scientific data. Methods Based on the data obtained from the 2019 Global Burden of Disease (GBD) database, the numbers and age-standardized rates (ASRs) of incidence, prevalence, death, and disability-adjusted life-years (DALYs) of Alzheimer's disease and other dementias from 1990 to 2019 were analyzed. Calculated estimated annual percentage changes (EAPCs) and Joinpoint regression analyses were performed to evaluate the trends during this period. We also evaluated the correlations between the epidemiology and the sociodemographic index (SDI), an indicator to evaluate the level of social development in a country or region considering the education rate, economic situation, and total fertility rate. Results From 1990 to 2019, the incidence and prevalence of Alzheimer's disease and other dementias increased by 147.95 and 160.84%, respectively. The ASR of incidence, prevalence, death, and DALYs in both men and women consistently increased over the study period. All the ASRs in women were consistently higher than those in men, but the increases were more pronounced in men. In addition, the ASRs of incidence, prevalence, and DALYs were positively correlated with the SDI. Moreover, the proportion of patients over 70 years old with dementia was also positively correlated with the SDI level. Smoking was a major risk factor for the disease burden of dementia in men, while obesity was the major risk factor for women. Conclusion From 1990 to 2019, the Alzheimer's disease burden increased worldwide. This trend was more serious in high-SDI areas, especially among elderly populations in high-SDI areas, who should receive additional attention. Policy-makers should take steps to reverse this situation. Notably, women were at a higher risk for the disease, but the risk in men showed a faster increase. We should give attention to the aging population, attach importance to interventions targeting dementia risk factors, and formulate action plans to address the increasing incidence of dementia.
... Regarding body weight changes, a difference was found between the two genotypes [F (3,59) = 12.59, p< 0.0001], the 3xTg-AD mice being heavier than the controls. However, OVX surgery itself increased the body weight during a 40-day period [F (1,19) = 16.35, ...
Article
Full-text available
Alzheimer’s disease is the most common type of dementia, being highly prevalent in elderly women. The advanced progression may be due to decreased hormone synthesis during post-menopause as estradiol and progesterone both have neuroprotective potentials. We aimed to confirm that female hormone depletion aggravates the progression of dementia in a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD). As pathological hallmarks are known to appear in 6-month-old animals, we expected to see disease-like changes in the 4-month-old 3xTg-AD mice only after hormone depletion. Three-month-old female 3xTg-AD mice were compared with their age-matched controls. As a menopause model, ovaries were removed (OVX or Sham surgery). After 1-month recovery, the body composition of the animals was measured by an MRI scan. The cognitive and anxiety parameters were evaluated by different behavioral tests, modeling different aspects (Y-maze, Morris water maze, open-field, social discrimination, elevated plus maze, light–dark box, fox odor, operant conditioning, and conditioned fear test). At the end of the experiment, uterus was collected, amyloid-β accumulation, and the cholinergic system in the brain was examined by immunohistochemistry. The uterus weight decreased, and the body weight increased significantly in the OVX animals. The MRI data showed that the body weight change can be due to fat accumulation. Moreover, OVX increased anxiety in control, but decreased in 3xTg-AD animals, the later genotype being more anxious by default based on the anxiety z-score. In general, 3xTg-AD mice moved less. In relation to cognition, neither the 3xTg-AD genotype nor OVX surgery impaired learning and memory in general. Despite no progression of dementia-like behavior after OVX, at the histological level, OVX aggravated the amyloid-β plaque deposition in the basolateral amygdala and induced early cholinergic neuronal fiber loss in the somatosensory cortex of the transgenic animals. We confirmed that OVX induced menopausal symptoms. Removal of the sexual steroids aggravated the appearance of AD-related alterations in the brain without significantly affecting the behavior. Thus, the OVX in young, 3-month-old 3xTg-AD mice might be a suitable model for testing the effect of new treatment options on structural changes; however, to reveal any beneficial effect on behavior, a later time point might be needed.
... Neuropsychiatric symptoms (NPS) are also particularly common in the course of the disease, affecting up to half of patients with Mild Cognitive Impairment (MCI) and nearly all patients with AD-dementia (11)(12)(13)(14). These symptoms mainly include depression, anxiety, psychosis, agitation, irritability and sleep disturbances, although apathy-described as loss of motivation, decreased interest and lack of emotional reactivity (15)-is the most common of these symptoms, with a prevalence in approximately 50% of MCI and 80% of AD patients (16)(17)(18)(19)(20). ...
Article
Full-text available
Neuropsychiatric symptoms (NPS) occur in nearly all patients with Alzheimer's Disease (AD). Most frequently they appear since the mild cognitive impairment (MCI) stage preceding clinical AD, and have a prognostic importance. Unfortunately, these symptoms also worsen the daily functioning of patients, increase caregiver stress and accelerate the disease progression from MCI to AD. Apathy and depression are the most common of these NPS, and much attention has been given in recent years to understand the biological mechanisms related to their appearance in AD. Although for many decades these symptoms have been known to be related to abnormalities of the dopaminergic ventral tegmental area (VTA), a direct association between deficits in the VTA and NPS in AD has never been investigated. Fortunately, this scenario is changing since recent studies using preclinical models of AD, and clinical studies in MCI and AD patients demonstrated a number of functional, structural and metabolic alterations affecting the VTA dopaminergic neurons and their mesocorticolimbic targets. These findings appear early, since the MCI stage, and seem to correlate with the appearance of NPS. Here, we provide an overview of the recent evidence directly linking the dopaminergic VTA with NPS in AD and propose a setting in which the precocious identification of dopaminergic deficits can be a helpful biomarker for early diagnosis. In this scenario, treatments of patients with dopaminergic drugs might slow down the disease progression and delay the impairment of daily living activities.
... AD is an age-related neurodegenerative disorder, with an insidious onset and deadly outcome. The clinical presentation of AD comprises memory loss and difficulties with thinking, speech, completing familiar tasks, and problem-solving skills [21,22]. The onset and progression of AD involves complex interactions of multiple factors. ...
Article
Full-text available
Alzheimer’s disease (AD), an age-related neurodegenerative disorder, is currently incurable. Imbalanced amyloid-beta (Aβ) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Historically, strategies targeting Aβ clearance have typically focused on central clearance, but with limited clinical success. Recently, the contribution of peripheral systems, particularly the liver, to Aβ clearance has sparked an increased interest. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. We further propose that compromised peripheral Aβ clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD.
... In an analysis of the National Alzheimer Coordinating Center data set, NPS emerged in advance of a cognitive diagnosis in 59% of dementia cases, including 30% of individuals who ultimately developed AD (Wise et al, 2019). Neuropsychiatric manifestations may include mood, perception, and behavior disturbances; agitation; lack of motivation; loss of initiative; apathy; social withdrawal; loss of interest for activities; loss of empathy; obsessive or compulsive behaviors; and socially improper behaviors (Lyketsos et al, 2002(Lyketsos et al, , 2011. ...
Article
Background: Alzheimer disease dementia may be preceded by cognitive stages during which behavioral and psychological changes can occur. More precisely, behavioral symptoms may be observed during the subjective cognitive decline (SCD) or the mild cognitive impairment (MCI) stages; these symptoms can be measured using the Mild Behavioral Impairment Checklist (MBI–C). Objective: To validate the French-Quebec version of the MBI–C in individuals ages 60–85 years. Method: The sample included 60 participants (20 MCI, 20 SCD, 20 cognitively healthy) and their informants. To assess the discriminant validity of the MBI–C, a Kruskal-Wallis analysis with a multiple comparisons test was performed on the MBI–C Total score. To determine convergent validity, Spearman correlations were calculated between the MBI–C subscales and a set of validation tools. Finally, test–retest reliability was assessed with Spearman correlations of MBI–C scores between two test sessions. Results: All of the analyses indicated satisfactory psychometric properties for the French-Quebec version of the MBI–C. Conclusion: This validation study reveals that the MBI–C can be used successfully in dementia risk assessments. From now on, the use of a validated MBI–C will be possible in the French-Quebec population.
... AD is a pathologically heterogeneous and biologically multilayered disease characterized by gradual memory loss and cognitive and behavioral dysfunctions [14], currently being re-conceptualized as a biological and clinical continuum [15][16][17] that extends from a long asymptomatic phase with evidence of AD pathology but normal cognitive function, to minor cognitive changes and, ultimately, reaching to a clinically symptomatic AD phase [18]. Although mainly considered a cognitive disorder, AD is often associated with neuropsychiatric disabilities, which manifest throughout different phases of the disease continuum [19]. AD patients may exhibit a plethora of neuropsychiatric impairments, greatly fluctuating in severity and frequency, including apathy, depression, anxiety, irritability, sleep disturbances, eating abnormalities, agitation, elation, hallucinations, delusions, motor disturbances, and disinhibition [20][21][22][23]. ...
Article
Full-text available
The Pinus L. genus comprises around 250 species, being popular worldwide for their medicinal and aromatic properties. The present study aimed to evaluate the P. halepensis Mill. essential oil (PNO) in an Alzheimer’s disease (AD) environment as an anxiolytic and antidepressant agent. The AD-like symptoms were induced in Wistar male rats by intracerebroventricular administration of amyloid beta1-42 (Aβ1-42), and PNO (1% and 3%) was delivered to Aβ1-42 pre-treated rats via inhalation route for 21 consecutive days, 30 min before behavioral assessments. The obtained results indicate PNO’s potential to relieve anxious–depressive features and to restore redox imbalance in the rats exhibiting AD-like neuropsychiatric impairments. Moreover, PNO presented beneficial effects against neuroinflammation and neuroapoptosis in the Aβ1-42 rat AD model.
... Alzheimer's disease (AD) is the leading cause of dementia in the elderly population, and AD is characterized by severe cognitive deficits, including memory loss and language impairment. In addition to cognitive deficits, neuropsychiatric symptoms such as depression, apathy, and hallucinations are often seen in patients with AD [129,130]. As a neurodegenerative disorder, the key pathological features of AD include neuronal loss and cellular dysfunction. ...
Article
Full-text available
Neuroligins are postsynaptic cell adhesion molecules that are relevant to many neurodevelopmental disorders. They are differentially enriched at the postsynapse and interact with their presynaptic ligands, neurexins, whose differential binding to neuroligins has been shown to regulate synaptogenesis, transmission, and other synaptic properties. The proper functioning of functional networks in the brain depends on the proper connection between neuronal synapses. Impaired synaptogenesis or synaptic transmission results in synaptic dysfunction, and these synaptic pathologies are the basis for many neurodevelopmental disorders. Deletions or mutations in the neuroligins genes have been found in patients with both autism and schizophrenia. It is because of the important role of neuroligins in synaptic connectivity and synaptic dysfunction that studies on neuroligins in the past have mainly focused on their expression in neurons. As studies on the expression of genes specific to various cells of the central nervous system deepened, neuroligins were found to be expressed in non-neuronal cells as well. In the central nervous system, glial cells are the most representative non-neuronal cells, which can also express neuroligins in large amounts, especially astrocytes and oligodendrocytes, and they are involved in the regulation of synaptic function, as are neuronal neuroligins. This review examines the mechanisms of neuron neuroligins and non-neuronal neuroligins in the central nervous system and also discusses the important role of neuroligins in the development of the central nervous system and neurodevelopmental disorders from the perspective of neuronal neuroligins and glial neuroligins.
Article
Major depressive disorder and Alzheimer's disease are common among older people, frequently co-occur and severely impact the quality of life. Unfortunately, data on the efficacy of pharmacologic treatment of depressive symptoms in patients with the neurodegenerative disease remain inconclusive. The heterogeneity of treatment study designs, from varying diagnostic specificity to diverse outcome measures, contributes to conflicting evidence across single trials and meta-analyses. In this literature review, we focus on commercially available products for antidepressant treatment in demented individuals and show how insights from randomized controlled trials could still guide and be aligned with common clinical practice.
Chapter
Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring. The new edition includes over 500 new or refreshed figures, an intuitive color scheme, fourteen new uses for older drugs and eighteen brand new drugs, coverage of Parkinson's Disease Psychosis, behavioural symptoms of dementia, and mixed features in major depressive episodes, and expanded information on the medical uses of cannabis and hallucinogen assisted psychotherapy.
Article
Full-text available
Alzheimer’s disease (AD), a neurodegenerative brain disorder that affects millions of people worldwide, is characterized by memory loss and cognitive decline. Low levels of acetylcholine and abnormal levels of beta-amyloid, T protein aggregation, inflammation, and oxidative stress, have been associated with AD, and therefore, research has been oriented towards the cholinergic system and primarily on acetylcholinesterase (AChE) inhibitors. In this review, we are focusing on the discovery of AChE inhibitors using computer-based modeling and simulation techniques, covering the recent literature from 2018–2022. More specifically, the review discusses the structures of novel, potent acetylcholinesterase inhibitors and their binding mode to AChE, as well as the physicochemical requirements for the design of potential AChE inhibitors.
Article
There is special interest in antidepressants as potential repurposing drugs for neurodegenerative disorders (ND). Microglia activation is implicated to play a causal role in the pathogenesis of ND. Furthermore, preclinical studies showed profound impact of antidepressants on microglial cells. However, the underlying mechanisms remain unclear. We carried out a systematic review and meta-analysis that investigated the effects of antidepressants on microglial cells. In total 89 studies were quantitatively reviewed and 24 in vitro and 28 in vivo studies were suitable for meta-analysis. Random-effects meta-analysis showed an overall significant decrease in microglial activation markers after antidepressant administration in cell studies, animal stress models, and animal LPS models. Also, 30 out of 31 animal disease models showed a decrease in microglial activation after antidepressant treatment. We did not observe significant differences when microglial cells were not activated prior to treatment. There is a robust anti-inflammatory effect of antidepressants in activated microglial cells in cell or animal studies. However, the summary of the effect could be an overestimation of the true effect since we observed high heterogeneity between studies, potential publication bias and control subjects were shared between different experimental groups. Microglia can respond differently depending on the underlying process. A next step will be to understand the effects of antidepressants on microglia activation in the human brain, and more specifically on activated microglia in different brain pathologies.
Chapter
The gastrointestinal tract is colonized by approximately a hundred trillion gut microorganisms consisting of more than thousands of species, including bacteria, viruses, and fungi, which are called gut microbiota. It is not only involved in food digestion, nutrient acquisition and energy regulation, but also participants in regulating brain activity and behavior via the gut-microbiota-brain axis. Accumulating evidence has revealed the association between gut dysbiosis and a series of neuropsychiatric diseases including neurological diseases such as Alzheimer’s disease, psychiatric disorders, such as schizophrenia, depression, and anxiety. The gut microbiota system modulates the bidirectional communication between gut and brain through the neuroanatomical, neuroendocrine, inflammatory, and metabolic pathways, as well as the barrier system consisted of gut mucosal barrier and blood–brain barrier. Mechanisms of gut microbiota mediated pathophysiological processes have indicated potential therapeutic targets for treating neuropsychiatric diseases. Treatment methods including the probiotics supplements, dietary intervention, fecal microbial transplantation, and microbial metabolism have been applied in both animal models and humans. This review focused on gut dysbiosis related neuropsychiatric diseases, roles of the microbiota-gut-brain axis, as well as the effectiveness of related treatment approaches.KeywordsBrain-Gut bidirectionalityNeuroendocrine systemFecal microbial transplantationNeuropsychiatric diseasesDietary modificationProbiotic supplementation
Preprint
Full-text available
Alzheimer's disease (AD) is associated with mitochondrial dysfunction and disturbances in neurotransmitter systems. Depression is a common comorbidity of AD, and the disruption of monoaminergic neurotransmission may be involved in the pathophysiology of AD. Assessment of mitochondrial dysfunction was performed by measuring mitochondrial respiratory rate; changes in monoamine neurotransmission were evaluated by measuring mitochondrial monoamine oxidase B (MAO-B) activity and serotonin transporter (SERT) activity in platelets. The decreases in the maximum capacity of the electron transport system and a decrease in the respiratory reserve capacity compared to controls was significant in intact platelets of AD patients but not in vascular dementia (VD) patients, indicating some specificity of these biomarkers for AD. In permeabilized platelets, parameters of mitochondrial respiration were not significantly altered in AD, suggesting that the reduction observed in intact platelets may be due to impaired availability of respiratory chain enzyme substrates. MAO-B activity and SERT activity were not significantly different between controls and AD and VD patients. The association of biochemical parameters with cognitive decline and comorbid depression in subjects with AD and VD showed the applicability of mitochondrial respiration in intact platelets, but not MAO-B activity and SERT activity, as a blood biomarker of AD.
Article
Full-text available
Background: Within the concept of the self, a distinction can be made between ideal self (i.e., what would like to become) and feared self (i.e., what would not like to become in the future). Objective: We investigated ideal self and feared self in patients with mild Alzheimer's disease (AD). We have also measured these self-related processes in relation to depression and anxiety. Methods: We invited 31 patients with mild AD and 35 control participants to decide whether they would consider the statement (e.g., I will be healthy) as a representation that they would like to acquire (i.e., ideal self) or to avoid (i.e., feared self). Results: Analysis demonstrated that more participants assigned the "I will be healthy" statement to ideal self than to feared self, and this tendency was observed in both AD participants and controls. Less depression and anxiety were observed in participants who have assigned the "I will be healthy" statement to their ideal self compared to those who assigned this statement to their feared self, and this was observed in both AD participant and control groups. Conclusion: Our study demonstrates that AD patients tend to endorse positive health traits and to integrate these traits into their ideal self. AD patients tend to endorse health-related images that are associated with hopes when projecting into their future self. This positive projection into the self may create a motivational force (e.g., aspirations and hopes) to embody the "healthy" self that AD patients desire to be.
Article
About 10 million new cases of dementia develop worldwide each year, of which up to 70% are attributable to Alzheimer's disease (AD). In addition to the widely known symptoms of memory loss and cognitive impairment, AD patients frequently develop non-cognitive symptoms, referred to as behavioral and psychological symptoms of dementia (BPSDs). Sleep disorders are often associated with AD, but mood alterations, notably depression and apathy, comprise the most frequent class of BPSDs. BPSDs negatively affect the lives of AD patients and their caregivers, and have a significant impact on public health systems and the economy. Because treatments currently available for AD are not disease-modifying and mainly aim to ameliorate some of the cognitive symptoms, elucidating the mechanisms underlying mood alterations and other BPSDs in AD may reveal novel avenues for progress in AD therapy. Purinergic signaling is implicated in the pathophysiology of several CNS disorders, such as AD, depression and sleep disorders. Here, we review recent findings indicating that purinergic receptors, mainly the A1, A2A, and P2X7 subtypes, are associated with the development/progression of AD. Current evidence suggests that targeting purinergic signaling may represent a promising therapeutic approach in AD and related conditions.
Article
Objectives This meta-analysis was aimed at systematically synthesizing the effects of exercise interventions on neuropsychiatric symptoms in individuals with dementia. The possible moderators that may influence intervention effects were also examined. Methods We searched seven databases (PubMed, Web of Science, SCOPUS, SportDiscus, Ebsco, China National Knowledge Infrastructure, and Wanfang) for randomized clinical trials. The pooled effect sizes were computed by the standardized mean difference (SMD) from post-intervention scores using random-effects models. Potential moderators were also explored by performing subgroup analyses and meta-regression. The risk of bias for included studies was evaluated by the Cochrane Risk of Bias 2.0 Tool. Results A total of 22 effect sizes from 17 studies (n = 1344) fulfilled the inclusion criteria. The results indicated that exercise interventions had a small but significant effect on neuropsychiatric symptoms in dementia (SMD = −0.27, 95% CI [−0.40,−0.14], p < 0.001). Subgroup analyses showed that intervention frequency and disease severity moderated the effects. Specifically, interventions with medium-frequency (3 times/week) had a positive effect on neuropsychiatric symptoms (SMD = −0.5, 95% CI [−0.65, −0.34], p < 0.001), but not with low-frequency (1–2 times/week) (SMD = −0.07, 95% CI [−0.22, 0.08], p = 0.38) or high-frequency (4–7 times/week) (SMD = −0.11, 95% CI [−0.36, 0.14], p = 0.38). Interventions had a beneficial effect on neuropsychiatric symptoms in people with mild dementia (SMD = −0.48, 95% CI [−0.71, −0.26], p < 0.001), and moderate dementia (SMD = −0.21, 95%CI [−0.37, 0.05], p < 0.05), but not severe dementia (SMD = −0.01, 95% CI [−0.33, 0.3], p = 0.94). Conclusions Exercise interventions effectively improve neuropsychiatric symptoms in mild and moderate dementia patients. Interventions occurring three times per week were associated with significant effects. Our findings provide evidence that exercise interventions may be an accessible and effective means for improving dementia patients' neuropsychiatric symptoms.
Article
Objectives A frequent late Alzheimer's Disease and Related Diseases (ADRD) identification is described and may induce erratic health resource use. We aimed to describe healthcare use patterns preceding ADRD identification. Methods We studied persons aged 65 or older, identified with incident ADRD in 2012 in the French health insurance database. Healthcare use covering a wide range of care in ambulatory and hospital settings during the period ranging from 18 to six months before ADRD identification was studied. The main dimensions of healthcare use patterns before ADRD identification were investigated in three age groups (65–74, 75–84, ≥85) through a multiple correspondence analysis. These dimensions were secondarily interpreted according to the 5-year healthcare trajectory following ADRD identification, qualified as favorable (or not) by experts in the field. Results This research studied 36,990 subjects. Four dimensions raised in each age group. Two dimensions' interpretations were retrieved in all age groups: intensity of healthcare use, functional dependency. However, their rank differed along with the qualification of the future healthcare trajectory. Some specificities appeared in some age group. In the 65–74 and 75–84 years groups, there were dimensions reflecting healthcare use related to psychiatric or psycho-behavioral disorders. In the ≥85 group, two dimensions reflected dependency related to other comorbidities, and organised medical follow-up. Conclusion Several dimensions emerged in line with erratic trajectories before ADRD identification. They underlined the need for actions towards ADRD identification.
Article
Objectives Because light can regulate sleep rhythms, numerous studies have investigated whether light therapy can improve sleep disorders in older people, but its efficacy remains controversial. Therefore, this systematic review aimed to examine and summarize current evidence about the efficacy of light therapy to improve sleep for older people in residential long-term care. Design Systematic review. Setting and participants Older people living in long-term care settings. Methods Systematic searches were conducted in the databases PubMed, Web of Science, Cochrane, EMBASE, CINAHL, China National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, Chinese Biomedical Literature Database, and in reference lists within relevant articles. Studies were eligible for inclusion if they evaluated light therapy for older people with sleep disorders in long-term care settings. Results This systematic review includes 21 articles, summarizing light therapy with different durations and intensities. The light intervention was typically administered between 7:00 and 12:00 am for 30-120 minutes. The interventions lasted from 1 week to several months, and the intensity of the light intervention usually ranged from 2500 to 10,000 lux. Short-term exposure (30-60 minutes) with high light levels (≥10,000 lux), relatively long-term exposure (1-2 hours) with moderate light levels (2500-10,000 lux), or long-term exposure (1-4 hours or full day) with low light levels (≤2500 lux) were associated with improved sleep indicators for older people in long-term care settings. Conclusions and implications The efficacy of light therapy in long-term care settings may be affected by the duration of exposure, time and length of intervention, intensity of light, and equipment used to administer the therapy. Further research must be conducted to optimize light therapy parameters. Large, high-quality randomized controlled trials are needed to deepen our understanding of the effects of light therapy on sleep in older people living in long-term care settings.
Article
Background Dementia-friendly community has been promoted in Macao since 2016. There is no study investigating the understanding of nor attitudes towards dementia among public contact staff in Macao. This study aimed to (i) understand the level of knowledge of dementia, (ii) examine the attitudes towards people living with dementia, and (iii) explore the associated factors of the willingness to help people with dementia symptoms among police officers, bank officers, bus drivers, and building superintendents. Methods A cross-sectional survey was conducted between January and May 2019 using a structured questionnaire. Results A total of 351 valid questionnaires were received. Building superintendents had more knowledge while police officers and bank officers had more positive attitudes. All practitioners were more willing to help people with dementia symptoms when they were on official duty. Participants who had more knowledge about dementia were associated with a higher willingness to help people with dementia symptoms.
Article
Objectives This study aimed to explore the behavioral and social impairments among people living with dementia (PLWD) in rural southwestern Uganda. It also explored the burden of caregivers for people living with dementia. Methods This was a qualitative study among people living with dementia and their caregivers. We consecutively enrolled 30 people living with dementia with their caregivers from their homes. We conducted in-depth interviews using a semi-structured interview guide. We did a thematic content analysis. Results The themes under-reported behavioral impairment were; difficulty in personal care, physical inactivity, and impaired judgment. Under the social and cognitive impairment theme, there was the failure to be in social gatherings like church, community groups, and markets. Under the caregivers’ role, their burden included managing behavioral, social, and cognitive impairments of PLWD. Although caregivers were committed to caring for PLWDs, this required sacrificing time at the expense of income-generating activities. Conclusions Dementia hinders the behavioral and social aspects of the affected people. Caregivers are highly burdened to care for PLWD. Strategies to minimize caregivers’ burden while caring for people living with dementia are recommended.
Article
The eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! Using Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. The new edition includes over 500 new or refreshed figures, an intuitive color scheme, 14 new uses for older drugs and 18 brand new drugs, coverage of Parkinson's Disease Psychosis, behavioural symptoms of dementia, and mixed features in major depressive episodes, and expanded information on the medical uses of cannabis and hallucinogen assisted psychotherapy. This product combines the fifth edition of the textbook with a one-year subscription to www.stahlonline.org, providing access to the full range of Dr Stahl's content. The one-year subscription is activated via a code provided with the printed book.
Article
[¹⁸F]BAY-94-9172, [¹⁸F]AV-45, and [¹⁸F]GE-067 were FDA approved positron emission tomography (PET) imaging radiotracer of β-amyloid plaques (Aβ) in Alzheimer’s disease (AD). However, the radiochemical synthesis requires multi-step reactions and complex procedure. Recently, a protocol for radiochemical synthesis of sulfur fluoride exchange (SuFEx) using ultrafast ¹⁹F/¹⁸F isotopic exchange had been reported. We developed three pairs of novel ¹⁸F-labeled radiotracers by the “SuFEx” method for PET imaging Aβ plaques. The ¹⁸F labeling reaction can be completed quickly (30 s) at room temperature and purified using solid-phase extraction (SPE). The radiochemical purity (RCP) of the products was all greater than 95%. In vitro fluorescent staining using Aβ-transgenesis mice section preliminary verified the affinity of tracers with Aβ. Competitive binding assay displayed high affinity of tracers for towards artificial Aβ1-42 aggregates (Ki values ranging from 3.53 ± 0.39 to 42.0 ± 4.24 nM). In vivo biodistribution and Micro-PET imaging showed that [¹⁸F]-Sulfur Fluoride β-Amyloid ([¹⁸F]SFA 1-6) could penetration the blood-brain barrier (BBB) in wild-type mice, and [¹⁸F]SFA 5-6 had a high initial brain uptake value (3.65 ± 0.9% and 5.07 ± 0.1% ID/g, respectively) and a fast washout (Brain uptake2 min/60 min = 4.15 and 4.61, respectively) from the brain. In vitro autoradiography demonstrated the affinity of the [¹⁸F]SFA 5-6 to Aβ plaques in AD human brain tissues. Our results suggested that [¹⁸F]SFA maybe a potential PET radiotracers for detecting Aβ in Alzheimer’s disease.
Article
Preliminary estimates suggest that current global health‐care systems lack the resource capacity to provide persons with dementia timely access to diagnosis, treatment, and care. There is an increasing need to improve timely identification of individuals who will likely progress to Alzheimer's disease (AD) dementia particularly among under‐represented, underserved, and vulnerable populations. The rapidly evolving area of bioinformatics of health system data and the emergence of fluid‐based biomarkers for pre‐symptomatic AD may provide an innovative strategic option for health system planners. A think‐tank style meeting entitled “The Campaign to Prevent Alzheimer's Disease Work Group on Community‐Based Detection and Assessment of Cognitive Decline” developed recommendations to guide future sustainability activities, public policy campaigns, and implementation pilots. The group identified and explored different pathways of community‐based detection using electronic health records, from different international health‐care systems, to detect and surveil individuals with early possible cognitive impairment.
Article
Full-text available
The future GCC-connected environmental risk factors expedited the progression of nCDs. Indeed, the emergence of AFs is becoming a global food security concern. AFs are lethal carcinogenic mycotoxins, causing damage to the liver, kidney, and gastrointestinal organs. Long-term exposure to AFs leads to liver cancer. Almost a variety of food commodities, crops, spices, herbaceous materials, nuts, and processed foods can be contaminated with AFs. In this regard, the primary sections of this review aim to cover influencing factors in the occurrence of AFs, the role of AFs in progression of nCDs, links between GCC/nCDs and exposure to AFs, frequency of AFs-based academic investigations, and world distribution of AFs. Next, the current trends in the application of PPs to alleviate AFs toxicity are discussed. Nearly, more than 20,000 published records indexed in scientific databases have been screened to find recent trends on AFs and application of PPs in AFs therapy. Accordingly, shifts in world climate, improper infrastructures for production/storage of food commodities, inconsistency of global polices on AFs permissible concentration in food/feed, and lack of the public awareness are accounting for a considerable proportion of AFs damages. AFs exhibited their toxic effects by triggering the progression of inflammation and oxidative/nitrosative stress, in turn, leading to the onset of nCDs. PPs could decrease AFs-associated oxidative stress, genotoxic, mutagenic, and carcinogenic effects by improving cellular antioxidant balance, regulation of signaling pathways, alleviating inflammatory responses, and modification of gene expression profile in a dose/time-reliant fashion. The administration of PPs alone displayed lower biological properties compared to co-treatment of these metabolites with AFs. This issue might highlight the therapeutic application of PPs than their preventative content. Flavonoids such as quercetin and oxidized tea phenolics, curcumin and resveratrol were the most studied anti-AFs PPs. Our literature review clearly disclosed that considering PPs in antioxidant therapies to alleviate complications of AFs requires improvement in their bioavailability, pharmacokinetics, tissue clearance, and off-target mode of action. Due to the emergencies in the elimination of AFs in food/feedstuffs, further large-scale clinical assessment of PPs to decrease the consequences of AFs is highly required.
Article
Background: Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261). Methods: Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size. Results: In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.
Article
Alzheimer's Disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation on AD-like symptoms and pathology in APP NL-G-F/NL-G-F mice, a mouse model of AD. The results show that tactile stimulation reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviours and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, tactile stimulation appears to be a promising non-invasive strategy for slowing the onset of dementia in aging animals. This article is protected by copyright. All rights reserved.
Article
Anxiety is a neuropsychiatric disturbance that is commonly manifested in various dementia forms involving Alzheimer's disease (AD). The mechanisms underlying AD-associated anxiety haven't clearly recognized the role of energy metabolism in anxiety represented by the amygdala's autophagic sensors; liver kinase B1 (LKB1)/adenosine monophosphate kinase (AMPK). Dapagliflozin (DAPA), a SGLT2 inhibitor, acts as an autophagic activator through LKB1 activation in several diseases including AD. Herein, the propitious yet undetected anxiolytic potential of DAPA as an autophagic enhancer was investigated in AD animal model with emphasis on amygdala's GABAergic neurotransmission and brain-derived neurotrophic factor (BDNF). Alzheimer's disease was induced by ovariectomy (OVX) along with seventy-days-D-galactose (D-Gal) administration (150 mg/kg/day, i.p). On the 43rd day of D-Gal injection, OVX/D-Gal-subjected rats received DAPA (1 mg/kg/day, p.o) alone or with dorsomorphin the AMPK inhibitor (DORSO, 25 μg/rat, i.v.). In the amygdala, LKB1/AMPK were activated by DAPA inducing GABAB2 receptor stimulation; an effect that was abrogated by DORSO. Dapagliflozin also replenished the amygdala GABA, NE, and 5-HT levels along with glutamate suppression. Moreover, DAPA triggered BDNF production with consequent activation of its receptor, TrkB through activating GABAB2-related downstream phospholipase C/diacylglycerol/protein kinase C (PLC/DAG/PKC) signaling. This may promote GABAA expression, verifying the crosstalk between GABAA and GABAB2. The DAPA's anxiolytic effect was visualized by improved behavioral traits in elevated plus maze together with amendment of amygdala’ histopathological abnormalities. Thus, the present study highlighted DAPA's anxiolytic effect which was attributed to GABAB2 activation and its function to induce BDNF/TrkB and GABAA expression through PLC/DAG/PKC pathway in AMPK-dependent manner.
Article
Full-text available
O genograma é a ferramenta mais importante para obter informações acerca do indivíduo e sua família. O uso desse instrumento é importante na compreensão do contexto nuclear em que os processos saúde/ doença ocorrem. O objetivo geral deste trabalho foi realizar um artigo científico baseado em um estudo de caso, através de um genograma de uma família atendida pela USAFA Noêmia em Praia Grande - SP. Trata- se de um estudo retrospectivo, realizado a partir de dados registrado em prontuário de 3 pacientes de uma família, atendidos no período de julho a agosto de 2021.O genograma possibilitou que a equipe de saúde tivesse uma visão mais nítida dos padrões e da relação familiar comum e que interferem no processo saúde-doença. O histórico familiar, trouxe informações sobre os vários papéis de seus membros e das diferentes gerações que compõem a família. As atividades preventivas pela equipe de saúde da família averiguaram as doenças tanto de caráter genético como psicossocial com tendência a se repetir na família.
Article
Background: Changed behaviours in residential aged care facilities (RACF) are frequently reported in the literature. How RACF staff routinely respond to these observed changed behaviours represents a significant gap. Objective: To analyse the frequency of changed behaviour reported within RACF behavioural report logs and to ascertain how staff typically manage these behaviours. Methods: Residents (N = 25) with varying levels of cognitive function were recruited from a 160 bed RACF in Queensland, Australia. A retrospective analysis of behavioural report logs was conducted to elucidate prevalence of reported changed behaviours as categorised by RACF staff. Thematic analysis of staff recorded behavioural mitigation strategies was used to categorise staff actions. A case analysis was also conducted to highlight the challenges faced by RACF staff managing persistent acute changed behaviours using identified common mitigation strategies. The STROBE guidelines were followed for reporting. Results: There were 395 behaviours recorded in a two-month period. Physical agitation, interfering while wandering, trying to get to inappropriate places, verbal refusal of care, physical aggression, and verbal disruption were most frequently reported by staff. Management strategies included redirection, PRN psychotropic medication, reassurance, routine care practices, offering of beverages, repositioning, and rarely analgesia. A 24-h case analysis highlighted how staff utilised redirection and multiple doses of a PRN benzodiazepine with limited effectiveness. Conclusion: This study reveals current mitigation strategies employed by RACF staff in response to acute changed behaviours often associated with dementia. Agitation and wandering are prevalent and are difficult for staff to manage effectively. Relevance to clinical practice: This study highlights that careful consideration should be taken to avoid overuse of PRN benzodiazepines in management of changed behaviours. Short-term mitigation strategies, such as redirection, may not be effective if underlying causes such as pain, physiological, mental, emotional, or social needs are not met. Patient and public contribution: A RACF participated in project design and review.
Chapter
In recent years, the fundamental variety and biological influence of pyridine and its derivatives make them fascinating aims for preparation. These versatile compounds can be found in several bioactive natural products, drugs, functional materials and have been known as important chemical and pharmaceutical agents. As a result, the synthesis of pyridines remains an attractive subject to industrial and synthetic chemists. Based on the aforementioned properties, in this chapter, the recent advances in the catalytic synthesis of pyridine and its derivatives are collected. Several heterogeneous and homogeneous catalytic methods such as acidic and basic catalysts, nanocatalysis, ionic liquids, and molten salts, supported catalysts, transition metal catalysis, organocatalysts, I2, etc. have been employed for the synthesis of pyridines. Furthermore, these interesting compounds were constructed by numerous protocols such as metal-free catalysis, classical heating, sonication, and microwave irradiation by using solvents or solvent-free conditions. Also, this chapter highlights regioselectivity, isolated yields, and reaction conditions for the catalytic synthesis of pyridine derivatives.
Chapter
Alzheimer's disease (AD) is currently the third most progressive neurodegenerative disorder people facing across globally. The brains of AD patients undergo significant changes because of damage in brain nerve cells in regions like learning, thinking, and cognitive functions (memory) and ensuing experiences memory loss and speech damage, etc. In this situation, they start to face difficulties in common activities such as trouble to recalling earlier conversations, names/events. Therefore, AD patients are become bed-bound and need help around the clock and can eventually lead to malignancy. The current therapeutic targets of AD include the amelioration of β-amyloid plaque, cholinesterase inhibitors, tau-protein hyper-phosphorylation, biometal dyshomeostasis, and oxidative stress. In this state, pyridine analogues have been accredited as a promising anti-Alzheimer therapeutic leads. Since donepezil and tacrine are two pyridine analogues in the FDA-approved five drugs for the preliminary treatment of AD. Further, pyridine is an important key template for the existence of several natural molecules such as Vitamin B3, β-picoline, quinoline, trigonelline, and coenzymes (e.g., NADP), etc. The Hantzsch synthesis, Emil Knoevenagel process, Aleksei Chichibabin, Bonnemann cyclization, Gattermann–Skita synthesis, and Ciamician–Dennstedt rearrangement are the well-known methods for the synthesis of pyridine analogues. The production of industrial-scale pyridine analogues became easier after the invention of Chichiban synthesis by Russian chemist “Aleksei Chichibabin” through inexpensive staring materials and a more efficient route that is still practiced. Thus, it expands the importance of pyridine analogues for the treatment of AD and hence further studies are recommended for the development of potent anti-Alzheimer drugs. Therefore, the present chapter describes the role of pyridine analogues and their recent developments in the management of multisyndrome AD.
Article
Full-text available
Background: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium. Methods: Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up. Results: Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.
Article
Full-text available
Neuropsychiatric symptoms (NPS) affect almost all patients with dementia and are a major focus of study and treatment. Accurate assessment of NPS through valid, sensitive and reliable measures is crucial. Although current NPS measures have many strengths, they also have some limitations (e.g. acquisition of data is limited to informants or caregivers as respondents, limited depth of items specific to moderate dementia). Therefore, we developed a revised version of the NPI, known as the NPI-C. The NPI-C includes expanded domains and items, and a clinician-rating methodology. This study evaluated the reliability and convergent validity of the NPI-C at ten international sites (seven languages). Face validity for 78 new items was obtained through a Delphi panel. A total of 128 dyads (caregivers/patients) from three severity categories of dementia (mild = 58, moderate = 49, severe = 21) were interviewed separately by two trained raters using two rating methods: the original NPI interview and a clinician-rated method. Rater 1 also administered four additional, established measures: the Apathy Evaluation Scale, the Brief Psychiatric Rating Scale, the Cohen-Mansfield Agitation Index, and the Cornell Scale for Depression in Dementia. Intraclass correlations were used to determine inter-rater reliability. Pearson correlations between the four relevant NPI-C domains and their corresponding outside measures were used for convergent validity. Inter-rater reliability was strong for most items. Convergent validity was moderate (apathy and agitation) to strong (hallucinations and delusions; agitation and aberrant vocalization; and depression) for clinician ratings in NPI-C domains. Overall, the NPI-C shows promise as a versatile tool which can accurately measure NPS and which uses a uniform scale system to facilitate data comparisons across studies.
Article
Full-text available
Sleep and wake in Alzheimer's disease (AD) are often fragmented as manifested by bouts of wakefulness at night and napping during the day. Management of sleep disturbances in AD is important because of their negative impact on both patients and caregivers. Pharmacological treatments, mainly sedative-hypnotics and antipsychotics, are often used but can be associated with significant adverse effects. Non-pharmacological treatments represent a beneficial alternative approach to the management of sleep disturbances in AD since they are associated with fewer adverse effects and their efficacy can be sustained after treatment has been completed. The aim of this article is to review non-pharmacological treatments, such as sleep hygiene, sleep restriction therapy (SRT), cognitive behavioral therapy (CBT), light therapy, and continuous positive airway pressure (CPAP), for the management of sleep/wake disturbances in AD.
Article
Full-text available
Depression frequently occurs in the elderly and in patients suffering from dementia. Its cause is largely unknown, but several studies point to a possible contribution of circadian rhythm disturbances. Post-mortem studies on aging, dementia and depression show impaired functioning of the suprachiasmatic nucleus (SCN) which is thought to be involved in the increased prevalence of day-night rhythm perturbations in these conditions. Bright light enhances neuronal activity in the SCN. Bright light therapy has beneficial effects on rhythms and mood in institutionalized moderate to advanced demented elderly. In spite of the fact that this is a potentially safe and inexpensive treatment option, no previous clinical trial evaluated the use of long-term daily light therapy to prevent worsening of sleep-wake rhythms and depressive symptoms in early to moderately demented home-dwelling elderly. This study investigates whether long-term daily bright light prevents worsening of sleep-wake rhythms and depressive symptoms in elderly people with memory complaints. Patients with early Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI) and Subjective Memory Complaints (SMC), between the ages of 50 and 75, are included in a randomized double-blind placebo-controlled trial. For the duration of two years, patients are exposed to approximately 10,000 lux in the active condition or approximately 300 lux in the placebo condition, daily, for two half-hour sessions at fixed times in the morning and evening. Neuropsychological, behavioral, physiological and endocrine measures are assessed at baseline and follow-up every five to six months. If bright light therapy attenuates the worsening of sleep-wake rhythms and depressive symptoms, it will provide a measure that is easy to implement in the homes of elderly people with memory complaints, to complement treatments with cholinesterase inhibitors, sleep medication or anti-depressants or as a stand-alone treatment. ISRCTN29863753.
Article
Full-text available
Determining the genetic architecture of late onset Alzheimer's disease remains an important research objective. One approach to the identification of novel genetic variants contributing to the disease is the classification of biologically meaningful subgroups within the larger late-onset Alzheimer's disease phenotype. The occurrence of psychotic symptoms in patients with late-onset Alzheimer's disease may identify one such group. We attempted to establish methods for the reliable assessment of psychotic symptoms in a large, geographically dispersed collection of families, multiply affected with late onset Alzheimer's disease, who were participants in the larger National Institute on Aging Late Onset Alzheimer's Disease Family Study; and to characterize the correlates and familial aggregation of psychosis within this cohort. We found that reliable assessments of psychotic symptoms during in-person or phone interviews were readily implemented. The presence of psychosis in late onset Alzheimer's disease was significantly associated with degree of cognitive impairment, and significantly, albeit modestly, correlated with the severity of other behavioural symptoms. Psychosis significantly aggregated within late onset Alzheimer's disease families suggesting that it may identify a genetically determined subgroup. Future studies should examine the linkage and association of psychosis with genetic variation within these families.
Article
Full-text available
A consecutive series of 79 patients with probable Alzheimer's disease were assessed with a structured psychiatric evaluation, and diagnoses of apathy and depression were made using standardized criteria. Three-dimensional MRI scans were obtained from all patients, and images were segmented into gray matter, white matter, and CSF. White matter hyperintensities were edited on segmented images, and lobar assignments (frontal, temporal, parietal, and occipital) were made based on Talairach coordinates. Patients with apathy showed a significantly larger volume of frontal white matter hyperintensities than patients without apathy. Patients with depression had a significantly larger volume of right parietal white matter hyperintensities than patients without depression. However, neither apathy nor depression was significantly associated with lobar gray or white matter atrophy. Frontal and right parietal white matter hyperintensities are the strongest brain structural correlates of apathy and depression in Alzheimer's disease.
Article
Full-text available
Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. European Commission; Ana Aslan International Foundation.
Article
Full-text available
Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms-atypical antipsychotics-have a modest but significant beneficial effect in the short-term treatment (over 6-12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics-preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.
Article
Full-text available
Patients with Alzheimer's disease need assistance and supervision of their daily activities. They survive for protracted periods of time, placing an extensive burden of care on the caregiver prior to the patient's death. The present study addressed the predictive value of behavior-related burden on Alzheimer's disease caregivers. 82 patients with probable Alzheimer's (73.7 +/- 8.1 years), and their primary caregivers (59.6 +/- 14.8 years, 81.5% women), were assessed. Cognitive impairment, neuropsychiatric symptoms, and dementia severity were assessed with Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR), respectively. Caregivers were given Zarit's Burden Interview and Carer Activity Inventory. Neuropsychiatric symptoms like delusions, hallucinations, restlessness, anxiety, euphoria, disinhibition, unusual motor behavior, sleep disturbances, and appetite alterations were the best caregiver burden predictors (NPI r = 0.482, p < 0.001). No correlation with cognition, disease stage, or negative neuropsychiatric symptoms (depression and apathy) was found. Increased caregiver burden was related to increased levels of patient behavioral disturbance. Of these symptoms, hallucinations, unusual (motor) behavior, and abnormal behavior at nighttime were the most significant. No correlation with neuropsychiatric symptoms such as apathy and depression was found. This may have relevance to appropriate interventions for caregivers.
Article
Full-text available
Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, at least for some patients. Behavioral symptoms in MCI are associated with a higher risk of dementia, but their association with dementia risk in patients without MCI is unknown. Mild behavioral impairment (MBI) refers to a late-life syndrome with prominent psychiatric and related behavioral symptoms in the absence of prominent cognitive symptoms that may also be a dementia prodrome. This study sought to compare MCI and MBI patients and to estimate the risk of dementia development in these 2 groups. Between January 2001 and January 2006, a consecutive series of 358 elderly (>or= 65 years old) patients (239 with MCI and 119 with MBI) presenting to an outpatient general hospital specialty clinic were followed for up to 5 years until conversion to dementia or censoring. Thirty-four percent of MCI patients and over 70% of patients with MBI developed dementia (log-rank p = .011). MBI patients without cognitive symptoms were more likely to develop dementia (log-rank p < .001). MBI patients were more likely to develop frontotemporal dementia (FTD) than dementia of the Alzheimer's type (DAT). MBI appears to be a transitional state between normal aging and dementia. MBI (specifically in those without cognitive symptoms) may confer a higher risk for dementia than MCI, and it is very likely an FTD prodrome in many cases. These findings have implications for the early detection, prevention, and treatment of patients with dementia in late life, by focusing the attention of researchers on the emergence of new behavioral symptoms.
Article
Full-text available
Agitation is common in people with dementia, is distressing to patients and stressful to their carers. Drugs used to treat the condition have the potential to cause particularly severe side effects in older people with dementia and have been associated with an increased death rate. Alternatives to drug treatment for agitation should be sought. The study aimed to assess the effects of bright light therapy on agitation and sleep in people with dementia. A single center randomized controlled trial of bright light therapy versus standard light was carried out. The study was completed prior to the mandatory registration of randomized controls on the clinical trials registry database and, owing to delays in writing up, retrospective registration was not completed. There was limited evidence of reduction in agitation in people on active treatment, sleep was improved and a suggestion of greater efficacy in the winter months. Bright light therapy is a potential alternative to drug treatment in people with dementia who are agitated.
Article
Full-text available
Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI). To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population. Cross-sectional study derived from an ongoing population-based prospective cohort study. The Mayo Clinic Study of Aging. We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition. Neuropsychiatric Inventory Questionnaire score. Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy. Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.
Article
Symptoms consistent with dysfunction of the frontal lobes can occur following traumatic brain injury (TBI) or other types of acquired brain injury (stroke, aneurysm). These symptoms can include problems with short-term memory, attention, planning, problem solving, impulsivity, disinhibition, poor motivation, and other behavioral and cognitive deficits ("frontal lobe syndrome"). These symptoms may respond to certain drugs, such as dopaminergic agents. This case series describes results of using amantadine in 7 patients with this type of symptom profile (6 with TBI, 1 with meningitis following sinus surgery). Patients received neuropsychiatric examinations and serial neuropsychological testing. All patients showed some degree of positive response. One had side effects that resolved upon discontinuation of drug. The rationale for using dopaminergics is discussed, and pertinent literature is reviewed.
Article
Objective: Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression. Methods: The Cochrane Library (2006 [3]), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences. Results: Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6-12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for response and remission were 1.40 (95% confidence interval [CI] 1.24-1.57, z = 5.45, N = 13, p <0.001) and 1.27 (CI 1.12-1.44, z = 3.67, N = 13, p <0.001), respectively, with significant heterogeneity for response and remission among the trials. Mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The OR for response was significantly higher in the 10-12 week trials (OR = 1.73, CI 1.42-2.09, z = 5.51, N = 5, p <0.001) than the 6-8 week trials (OR = 1.22, CI 1.05-1.42, z = 2.60, N = 8, p = 0.01). ORs for discontinuation for any reason and for adverse events were significantly higher with drugs than with placebo. Conclusions: Antidepressants are more effective than placebo in elderly depressed subjects although effects are modest and vary. Identification of the characteristics of responders and nonresponders will be crucial to improving treatment outcomes.
Article
Low-dose methylphenidate was prescribed in an attempt to reverse the anorexia secondary to the gradual onset of apathetic behavior in three severely demented, long-term institutionalized geriatric patients. The anorexia was alleviated quickly in each case without appreciable side effects, and the benefit lasted for a prolonged period after cessation of the psychostimulant. Copyright (C) 1993 American Association for Geriatric Psychiatry
Article
Objective We investigated the frequency and inter-relationship of neuropsychiatric disturbances in a population sample of persons suffering from Alzheimer's disease (AD).Method Screening 5,092 elderly residents (90% of the population aged 65 and older) of Cache County, Utah, for dementia, we identified 198 persons with AD using a comprehensive neuropsychiatric examination protocol. This examination included the Neuropsychiatric Inventory (NPI), a widely used measure of dementia-associated neuropsychiatric disturbances.ResultsOverall, 60% of individuals with AD reported one or more neuropsychiatric symptoms. A latent class analysis revealed that these participants could be classified into three groups (classes) based on their neuropsychiatric symptom profile. The largest class included cases with no neuropsychiatric symptoms (40%) or with a mono-symptomatic disturbance (19%). A second class (28%) exhibited a predominantly affective syndrome, while a third class (13%) had a psychotic syndrome.Conclusion Data from this first US population-based study of AD-associated neuropsychiatric disturbances suggest that a significant majority of persons with AD suffer from one or more neuropsychiatric disturbance. Based on phenomenological study, the spectrum of neuropsychiatric symptoms in AD can be empirically classified into three groups: an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbance. The biologic and predictive validity of this classification merits further investigation. Copyright © 2001 John Wiley & Sons, Ltd.
Article
Background: Agitation and aggression are common neuropsychiatric symptoms of Alzheimer's disease (AD) with a negative impact on caregivers. Objective: The aim of the study was to determine whether changes in agitation and aggression would follow memantine treatment and, if so, be associated with changes in nursing burden in institutionalized patients with moderate to severe AD. Study design: This was a 3-month open-label trial of memantine. Setting: The setting was two long-term care facilities. Patients: Thirty-one institutionalized patients with moderate to severe AD and significant behavioural and psychiatric symptoms were included in the study. Intervention: Memantine was titrated to a target dose of 10 mg twice daily. Main outcome measure: Effectiveness was assessed by the change in the Neuropsychiatric Inventory-Nursing Home (NPI-NH) agitation/aggression subscale and Clinical Global Impression of Change (CGI-C) scale using the intent-to-treat population. To establish caregiver impact, the effect on nursing burden was measured by the Modified Nursing Care Assessment Scale (primary outcome). As a secondary analysis, the caregiver distress subscale of the NPI-NH was examined, as well as changes in as required (pro re nata [prn]) psychotropic medication use. Results: Twenty-four patients completed the study. A significant decrease in agitation and aggression (F-test with 3 and 90 degrees of freedom [F(3,90)] = 3.721, p = 0.014) was demonstrated following memantine, with 48% of patients improving (either much improved or minimally improved) on the CGI-C scale. In addition, nursing burden (t-test with 30 degrees of freedom [t(30)] = 3.02, p = 0.005), caregiver distress (F(3,90) = 4.125, p = 0.009) and the use of prn psychotropics decreased following memantine treatment (Z = -1.99, p = 0.046). Fourteen patients experienced at least one adverse event during memantine treatment. The most common adverse event associated with treatment was somnolence (n = 5). Conclusion: The results of this study suggest that the decreased agitated and aggressive behaviour in institutionalized patients with moderate to severe AD following treatment with memantine was accompanied by improvements in nursing burden and decreased psychotropic use. These findings should be confirmed in a larger, controlled trial.
Article
The increasing prevalence of dementia will precipitate a significant burden in terms of the costs of caring for people with dementia over the next 30 years; sleep disturbances in dementia are an important factor contributing to this burden. We reviewed sleep disturbances in people with dementia and their carers and describe the various diagnostic, assessment and treatment strategies available to physicians in the management of this clinically significant problem. Sleep disturbances in people with dementia and their carers (i) are highly prevalent; (ii) impact significantly on quality of life of both people with dementia and their carers; (iii) increase the rate of cognitive decline; and (iv) accelerate the breakdown of community-based care. The training of physicians in the assessment and treatment of sleep disturbances in dementia and caregiving is scant despite a wide range of assessment strategies and treatment approaches, which comprise both pharmacological (including hypnotic/sedative medications) and non-pharmacological approaches (including: environmental; psychobehavioral; exercise and activity; and multi-component interventions). Specific diagnostic criteria for sleep disturbances in people with dementia and their carers remain lacking despite established criteria for general insomnia. Further to this, proposed changes to diagnostic criteria for DSM-V do not include a specific focus for the diagnosis and management of sleep disturbances in people with dementia or their carers. This review suggests that the improved training of physicians to meet the needs of these vulnerable groups of older people is a priority, especially in the context of a rapidly increasing demand for accurate, early diagnosis and efficient management of sleep disturbance in these groups.
Article
Apathy has been reported as the most prevalent behavioural symptom experienced in Alzheimer's disease (AD), associated with greater functional decline and caregiver distress. The aim of the current study was to investigate structural correlates of apathy in AD using magnetic resonance imaging (MRI) regional volume and regional cortical thickness measures. Semi-structured interviews were conducted with 111 AD patients and their caregivers as part of the European multi-centre study AddNeuroMed. Apathy was measured using the apathy domain of the Neuropsychiatric Inventory (NPI). All AD patients were scanned using a 1.5T MRI scanner and the images analysed using an automated analysis pipeline. We found apathy to be the most prevalent neuropsychiatric symptom occurring in 57% of patients. Apathetic patients had significantly greater cortical thinning in left caudal anterior cingulate cortex (ACC) and left lateral orbitofrontal cortex (OFC), as well as left superior and ventrolateral frontal regions, than those without apathy symptoms. Apathy is mediated by frontocortical structures but this is specific to the left hemisphere at least for patients in the mild to moderate stages of AD.
Article
Insomnia is a common problem among older adults. In particular, older adults experience insomnia coupled with early morning awakenings due to an interaction between age-related changes in circadian rhythm timing coupled with behavior changes that contribute to sustained poor sleep. Cognitive-behavioral therapy for insomnia (CBT-I), at times coupled with circadian interventions (e.g., timed light exposure), are likely to be most successful in optimizing sleep quality. In delivering CBT-I to older adults, modifications are sometimes necessary to accommodate for medical problems, lifestyle, social factors, and patient preferences. Addition of circadian interventions can ameliorate the negative effects of inappropriately timed sleep as well. These treatment methods can be highly effective and benefits can be long-standing. A case example is used to illustrate these points.
Article
Mild cognitive impairment (MCI) is a syndrome thought to be a prodrome of dementia for some patients. One subtype, amnestic MCI (aMCI), may be specifically predispose patients to develop Alzheimer's dementia (AD). Since dementia has been associated with a range of neuropsychiatric symptoms (NPS), we sought to examine the prevalence of NPS in MCI and its subtypes. One thousand seven hundred seventy-nine participants in the National Alzheimer's Coordinating Center (NACC) with MCI were included in this study. All participants were evaluated systematically with a thorough cognitive battery, clinical interview, and consensus diagnoses, and subtyped as: (1) amnestic (aMCI) (single- or multiple-domain) versus non-amnestic (non-aMCI); (2) executive dysfunction-MCI (exMCI) (single- or multiple-domain) versus no executive dysfunction-MCI (non-exMCI); (3) both aMCI and exMCI; and (4) neither aMCI nor exMCI. Additionally, aMCI versus non-aMCI and exMCI versus non-exMCI dichotomies were explored. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS). 1379 participants (77.5%) met criteria for aMCI and 616 (34.6%) for exMCI. No differences were observed in the prevalence of NPS between aMCI versus non-aMCI. However, exMCI was associated with greater severity of depression, anxiety, agitation, disinhibition, irritability, and sleep problems, although these differences do not persist after adjustment for multiple comparisons. While there were few associations between aMCI and NPS, the presence of executive dysfunction in MCI was associated with greater severity of symptoms and specifically with depression (evidenced by GDS score) and anxiety. These findings may have implications for MCI prognosis and need to be explored in longitudinal studies.
Article
To test the effects of an intervention that helps families manage distressing behaviors in family members with dementia. Two-group randomized trial. In home. Two hundred seventy-two caregivers and people with dementia. Up to 11 home and telephone contacts over 16 weeks by health professionals who identified potential triggers of patient behaviors, including communication and environmental factors and patient undiagnosed medical conditions (by obtaining blood and urine samples) and trained caregivers in strategies to modify triggers and reduce their upset. Between 16 and 24 weeks, three telephone contacts reinforced strategy use. Primary outcomes were frequency of targeted problem behavior and caregiver upset with and confidence managing it at 16 weeks. Secondary outcomes were caregiver well-being and management skills at 16 and 24 weeks and caregiver perceived benefits. Prevalence of medical conditions for intervention patients were also examined. At 16 weeks, 67.5% of intervention caregivers reported improvement in targeted problem behavior, compared with 45.8% of caregivers in a no-treatment control group (P=.002), and reduced upset with (P=.03) and enhanced confidence managing (P=.01) the behavior. Additionally, intervention caregivers reported less upset with all problem behaviors (P=.001), less negative communication (P=.02), less burden (P=.05), and better well-being (P=.001) than controls. Fewer intervention caregivers had depressive symptoms (53.0%) than control group caregivers (67.8%, P=.02). Similar caregiver outcomes occurred at 24 weeks. Intervention caregivers perceived more study benefits (P<.05), including ability to keep family members home, than controls. Blood and urine samples of intervention patients with dementia showed that 40 (34.1%) had undiagnosed illnesses requiring physician follow-up. Targeting behaviors upsetting to caregivers and modifying potential triggers improves symptomatology in people with dementia and caregiver well-being and skills.
Article
Alzheimer's disease (AD) is characterized by a number of serious and debilitating behavioral and psychological symptoms of dementia (BPSD). The most common of these BPSD is apathy, which represents a major source of morbidity and premature institutionalization in the AD population. Many studies have identified discrete changes to the dopaminergic (DAergic) system in patients with AD. The DAergic system is closely related to the brain reward system (BRS) and some studies have suggested that dysfunction in the DAergic system may account for symptoms of apathy in the AD population. Changes to the dopamine (DA) system in AD will be reviewed, and evidence supporting the involvement of the DAergic system in the development of apathy will be examined. Additionally, some pharmacological interventions with DA activity have been identified. The utility of these treatments in the AD population will be reviewed, with a focus on apathy as an outcome. Evidence presented in this review suggests that DA dysfunction in discrete brain areas is an important correlate of apathy in AD and that the DAergic system may be a rational target for pharmacological treatment of apathy.
Article
Depression is common in patients with Parkinson's disease, but evidence on the efficacy of antidepressants in this population is lacking. Because depression in patients with Parkinson's disease might be related to dopaminergic dysfunction, we aimed to assess the efficacy of the dopamine agonist pramipexole for treatment of depressive symptoms in patients with Parkinson's disease. We did a 12-week randomised, double-blind, placebo-controlled (1:1 ratio) trial of pramipexole (0.125-1.0 mg three times per day) compared with placebo in patients with mild-to-moderate Parkinson's disease. Patients from 76 centres in 12 European countries and South Africa were included if they were on stable antiparkinsonian therapy without motor fluctuations and had depressive symptoms (15-item geriatric depression scale score > or =5 and unified Parkinson's disease rating scale [UPDRS] part 1 depression item score > or =2). Patients were randomly assigned by centre in blocks of four by use of a randomisation number generating system. Clinical monitors, the principal investigator, and patients were masked to treatment allocation. The primary endpoint was change in Beck depression inventory (BDI) score and all treated patients who had at least one post-baseline efficacy assessment were included in the primary analysis. We also did a pre-specified path analysis with regression models to assess the relation between BDI and UPDRS part 3 (motor score) changes. This trial is registered with ClinicalTrials.gov, number NCT00297778, and EudraCT, number 2005-003788-22. Between March, 2006, and February, 2008, we enrolled 323 patients. Of 296 patients randomly assigned to pramipexole or placebo, 287 were included in the primary analysis: 139 in the pramipexole group and 148 in the placebo group. BDI scores decreased by an adjusted mean 5.9 (SE 0.5) points in the pramipexole group and 4.0 (0.5) points in the placebo group (difference 1.9, 95% CI 0.5-3.4; p=0.01, ANCOVA). The UPDRS motor score decreased by an adjusted mean 4.4 (0.6) points in the pramipexole group and 2.2 (0.5) points in the placebo group (difference 2.2, 95% CI 0.7-3.7; p=0.003, ANCOVA). Path analysis showed the direct effect of pramipexole on depressive symptoms accounted for 80% of total treatment effect (p=0.04). Adverse events were reported in 105 of 144 patients in the pramipexole group and 101 of 152 in the placebo group. Adverse events in the pramipexole group were consistent with the known safety profile of the drug. Pramipexole improved depressive symptoms in patients with Parkinson's disease, mainly through a direct antidepressant effect. This effect should be considered in the clinical management of patients with Parkinson's disease.
Article
To examine the temporal association between depressive symptoms and cognitive functioning and estimate the effect measure modification of the apolipoprotein E (APOE) epsilon4 allele on this relationship. Prospective cohort study. General community. Population-based sample of 598 cognitively intact older adults aged 60 and older, with re-assessments after 3 (N=479) and 6 years (N=412). Depressive symptoms (Symptom Checklist) and neurocognitive functioning (memory, Visual Verbal Learning Test; attention, Stroop Color-Word Test; processing speed, Letter Digit Substitution Test; general cognition, Mini-Mental State Examination). Longitudinal associations were assessed using linear mixed models. The risk for cognitive impairment, no dementia (CIND) was examined using logistic regression. Adjusting for age, sex, education, and baseline cognition, the rate of change in memory z-scores was 0.00, -0.11, -0.20, and -0.37 for those in the lowest (reference group), second, third, and highest depressive symptom quartiles at baseline, respectively (P<.001 for highest vs lowest quartile). The odds ratios for developing CIND with amnestic features were 1.00, 0.87, 0.69, and 2.98 for the four severity groups (P=.05 for highest vs lowest quartile). Associations were strongest for those with persistent depressive symptoms, defined as high depressive symptoms at baseline and at least one follow-up visit. Results were similar for processing speed and global cognitive function but were not as strong for attention. No APOE interaction was observed. Depression and APOE act independently to increase the risk for cognitive decline and may provide targets for prevention and early treatment.