Associations between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People.

BACKGROUND: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment. OBJECTIVE: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment. METHODS: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated. RESULTS: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03). CONCLUSION: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.

Group and individual cognitive therapies in Alzheimer's disease: the ETNA3 randomized trial.

BACKGROUND: Although non-drug interventions are widely used in patients with Alzheimer's disease, few large scale randomized trials involving a long-term intervention and several cognitive-oriented approaches have been carried out. ETNA3 trial compares the effect of cognitive training, reminiscence therapy, and an individualized cognitive rehabilitation program in Alzheimer's disease to usual care. METHODS: This is a multicenter (40 French clinical sites) randomized, parallel-group trial, with a two-year follow-up comparing groups receiving standardized programs of cognitive training (group sessions), reminiscence therapy (group sessions), individualized cognitive rehabilitation program (individual sessions), and usual care (reference group). Six hundred fifty-three outpatients with Alzheimer's disease were recruited. The primary efficacy outcome was the rate of survival without moderately severe to severe dementia at two years. Secondary outcomes were cognitive impairment, functional disability, behavioral disturbance, apathy, quality of life, depression, caregiver's burden, and resource utilization. RESULTS: No impact on the primary efficacy measure was evidenced. For the two group interventions (i.e. cognitive training and reminiscence), none of the secondary outcomes differed from usual care. The larger effect was seen with individualized cognitive rehabilitation in which significantly lower functional disability and a six-month delay in institutionalization at two years were evidenced. CONCLUSIONS: These findings challenge current management practices of Alzheimer's patients. While cognitive-oriented group therapies have gained popularity, this trial does not show improvement for the patients. The individualized cognitive rehabilitation intervention provided clinically significant results. Individual interventions should be considered to delay institutionalization in Alzheimer's disease.

'Kitchen and cooking,' a serious game for mild cognitive impairment and Alzheimer's disease: a pilot study.

Recently there has been a growing interest in employing serious games (SGs) for the assessment and rehabilitation of elderly people with mild cognitive impairment (MCI), Alzheimer's disease (AD), and related disorders. In the present study we examined the acceptability of 'Kitchen and cooking' - a SG developed in the context of the EU project VERVE (http://www.verveconsortium.eu/) - in these populations. In this game a cooking plot is employed to assess and stimulate executive functions (such as planning abilities) and praxis. The game is installed on a tablet, to be flexibly employed at home and in nursing homes. Twenty one elderly participants (9 MCI and 12 AD, including 14 outpatients and 7 patients living in nursing homes, as well as 11 apathetic and 10 non-apathetic) took part in a 1-month trail, including a clinical and neuropsychological assessment, and 4-week training where the participants were free to play as long as they wanted on a personal tablet. During the training, participants met once a week with a clinician in order to fill in self-report questionnaires assessing their overall game experience (including acceptability, motivation, and perceived emotions). The results of the self reports and of the data concerning game performance (e.g., time spent playing, number of errors, etc) confirm the overall acceptability of Kitchen and cooking for both patients with MCI and patients with AD and related disorders, and the utility to employ it for training purposes. Interestingly, the results confirm that the game is adapted also to apathetic patients.

Apathy in Neurodegenerative Diseases: Recommendations on the Design of Clinical Trials.

Apathy is a common feature of neurodegenerative disorders but is difficult to study in a clinical trial setting due to practical and conceptual barriers. Principal challenges include a paucity of data regarding apathy in these disorders, an absence of established diagnostic criteria, the presence of confounding factors (eg, coexisting depression), use of concomitant medications, and an absence of a gold-standard apathy assessment scale. Based on a literature search and ongoing collaboration among the authors, we present recommendations for the design of future clinical trials of apathy, suggesting Alzheimer disease and Parkinson disease as models with relevance across a wider array of neuropsychiatric disorders. Recommendations address clarification of the targeted study population (apathy diagnosis and severity at baseline), confounding factors (mood/cognition, behavior, and treatment), outcome measures, study duration, use of comparators and considerations around environment, and the role of the caregiver and patient assent. This review contributes to the search for an optimal approach to study treatment of apathy in neuropsychiatric disorders.

Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty.

Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.

Actigraphic motor activity in mild cognitive impairment patients carrying out short functional activity tasks: comparison between mild cognitive impairment with and without depressive symptoms.

BACKGROUND: Individuals with mild cognitive impairment (MCI) may exhibit changes in motor activity in conducting their activities of daily living. Depression, one of the most frequent neuropsychiatric symptoms, might affect motor activity in MCI. OBJECTIVE: To assess motor activity in MCI subjects carrying out short functional activity tasks using ambulatory actigraphy. Secondly, we sought to investigate the influence of depressive symptoms on motor activity. METHODS: 20 MCI and 14 healthy subjects carried out a 30-minute standardized scenario while wearing a chest actigraph. The protocol consisted of directed activities (execution of motor tasks), semi-directed activities (execution of Instrumental Activities of Daily Living, IADL), and undirected 'free' activities. Several common assessment scales (GDS, MADRS, and NPI) were used to diagnose depression. RESULTS: MCI subjects had significantly reduced mean motor activity while carrying out directed and semi-directed activities, compared to healthy control subjects. No difference was found in motor activity between MCI subjects with or without depression. CONCLUSION: Actigraphic measurement of motor activity during the evaluation of IADLs and motor tasks is a potential objective tool in detecting early changes in MCI. Depressive symptoms seem not to be associated with motor activity in MCI subjects.

Phenotyping apathy in individuals with Alzheimer disease using functional principal component analysis.

OBJECTIVES: To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD). DESIGN: Examination of ad libitum 24-hour ambulatory gross motor activity patterns. SETTING: Community-dwelling, outpatient. PARTICIPANTS: Ninety-two individuals with AD, 35 of whom had apathy. MEASUREMENTS: Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA). RESULTS: Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test). CONCLUSIONS: There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.

Validation of the Brazilian version of the apathy inventory.

BACKGROUND: Apathy is a frequent neuropsychiatric condition in neurodegenerative disorders, depression, and often in mild cognitive impairment. The Apathy Inventory (AI) is a reliable instrument for improving the accuracy of the apathy diagnosis. The aim was to establish the validity of the Apathy Inventory for the Brazilian community. METHODS: We established the concurrent validity, internal consistency, inter-rater reliability, and the sensitivity and specificity of AI for the Brazilian community in a cohort of 175 individuals with Alzheimer's disease, Parkinson's disease, depression, mild cognitive impairment, and healthy controls. The three dimensions of the AI (emotional blunting, lack of initiative, and lack of interest) were compared with the Apathy domain of the Neuropsychiatric Inventory-Clinician rating scale (NPI-C) in an independent scheme. RESULTS: The analyses demonstrated high correlation coefficients in AI's individual dimensions and in AI-total score (F = 0.965). Concerning the NPI-C/Apathy domain, intra-class correlation coefficients were also high (F = 0.977). Concurrent validity was high according to both raters on AI dimensions × NPI-C/Apathy domain and regarding total score (rater 1: rho = 0.956 vs. rater 2: rho = 0.970). The internal consistency of the AI was also high concerning the AI's individual dimensions and total score (rater 1: 0.945 vs. rater 2: 0.958). CONCLUSION: We observed high internal consistency, high concurrent validity, and inter-rater reliability of the Apathy Inventory. In addition, we found that its sensitivity and specificity were high. We suggest that the Brazilian version of the Apathy Inventory would be an appropriate instrument to identify the apathy syndrome in Brazilian patients.

Decreased daytime motor activity associated with apathy in Alzheimer disease: an actigraphic study.

OBJECTIVE: Across all stages of Alzheimer disease (AD), apathy is the most common neuropsychiatric symptom. Studies using the Neuropsychiatric Inventory (NPI) have found that apathy is present in up to 70% of individuals with Alzheimer disease. One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of reliable, objective measures. Motor activity assessment using ambulatory actigraphy could provide an indirect, objective evaluation of apathy. The aim of our study was to assess the relationship between apathy and daytime motor activity in AD, using ambulatory actigraphy. METHODS: One hundred seven AD outpatients wore a wrist actigraph (Motionlogger) during seven consecutive 24-hour periods to evaluate motor activity. Participants were divided into two subgroups according to their apathy subscores on the NPI: individuals with apathy (NPI-apathy subscores >4) and those without. Daytime mean motor activity scores were compared between the two subgroups. RESULTS: Individuals with AD who had symptoms of apathy (n = 43; age = 79 ± 4.7 years; Mini-Mental State Examination = 20.9 ± 4.8) had significantly lower daytime mean motor activity than AD patients without apathy (n = 64; age = 76.3 ± 7.7; Mini-Mental State Examination = 21.5 ± 4.7), while nighttime mean motor activity did not significantly differ between the two subgroups. CONCLUSIONS: Ambulatory actigraphy could be added to currently used questionnaires as a simple, objective technique for assessing apathy in the routine assessment of AD patients.

Imaging correlates of apathy and depression in Parkinson's disease.

Though the core symptoms of Parkinson's disease (PD) are motor-related, a majority of patients also have neuropsychiatric symptoms concerning mood, behavior and cognition. Apathy and depression are considered among the most frequent ones, and have a negative impact on global functioning and quality of life. Recent neuroimaging studies have provided specific findings related with these symptoms. Depression in PD has been specifically associated with morphological and functional changes in prefrontal cortex, cingulate and thalamus, as with 5-HT transmission reduction in posterior cingulated and amygdala-hippocampus complex. Apathy has received less attention, but has been related with gray matter volume reductions or functional deficits in many regions, as anterior and posterior cingulate and dorsolateral or inferior frontal gyrus. Some of these deficits may be also related with a more pronounced reduction in striatal dopamine transmission. As neuroimaging studies give more arguments to the mechanisms of these symptoms, they also stimulate research for a better individualization of specific affective dimensions in Parkinson's disease.

Lack of Association Between COMT Polymorphisms and Apathy in Alzheimer's Disease.

We tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD). We analyzed a cohort of 105 Caucasian individuals with AD (age = 79.3 ± 7.03 years; MMSE = 20.2 ± 4.4) according to the presence of apathy, as defined either by the Neuropsychiatric Inventory or the Apathy Inventory. Polymorphisms in seventeen SNPs in COMT were examined. A replication cohort consisting of 176 Caucasian AD subjects in the ADNI database was also analyzed. None of the candidate gene SNPs were significantly associated with the presence of apathy in either cohort. We did not find any SNPs in COMT that were consistently associated with apathy in individuals with AD.

AMPA workshop on challenges faced by investigators conducting Alzheimer's disease clinical trials.

The recruitment and retention of patients are among the greatest challenges currently being faced by researchers who conduct Alzheimer's disease (AD) clinical trials. To discuss these challenges and other major issues associated with clinical research in AD, an international workshop was organized by the Association Monégasque pour la recherche sur la Maladie d'Alzheimer at Monte Carlo, Monaco, in February 2010, with the participation of leading research experts in the field of Alzheimer's. Key topics discussed were as follows: (1) the selection, recruitment, and retention of clinical trial subjects; (2) international co-operation among researchers; and (3) patient rights and informed consent for participants in clinical trials. This article highlights some of the challenges faced by investigators when conducting clinical trials in AD, and it also offers some recommendations aimed at overcoming these challenges.

Effects of different learning methods for instrumental activities of daily living in patients with Alzheimer's dementia: a pilot study.

We examined whether errorless learning (EL) and learning by modeling (LM) were more advantageous than trial and error learning (TEL) in the acquisition of instrumental activities of daily living (IADL) in Alzheimer's dementia (AD) patients (n = 14). Using a counterbalanced within-subject design, participants performed 3 learning conditions. EL consisted of straightforward prompts before any action, LM focused on the modeling of each step of the tasks and standard TEL without cues was used as a control condition. The participants had to (re)learn 3 IADL. Repeated-measure analyses during learning and follow-up assessments were performed 1 and 3 weeks after learning. The LM and the EL procedures resulted in significantly better learning compared to TEL, with effect sizes (partial eta squared) of 0.42 and 0.35, respectively. This is the first controlled study to show that (re)learning of IADL is possible in patients with AD using an error-reduction approach.

Relationship between apathy and sleep disturbance in mild and moderate Alzheimer's disease: an actigraphic study.

Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer's disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. One hundred and three non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h periods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE = 21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy.

REVIEW: Apathy diagnosis, assessment, and treatment in Alzheimer's disease.

Apathy is defined as a disorder of motivation. There is wide acknowledgement that apathy is an important behavioral syndrome in Alzheimer's disease and in various neuropsychiatric disorders. In light of recent research and the renewed interest in the correlates and impacts of apathy and in its treatments, it is important to develop criteria for apathy that will be widely accepted, have clear operational steps, and be easy to apply in clinical practice and in research settings. Meeting these needs was the focus for a task force that included members of the European Psychiatric Association, the European Alzheimer's Disease Consortium and experts from Europe, Australia and North America.

Measurement of Neuropsychiatric Symptoms in Clinical Trials Targeting Alzheimer's Disease and Related Disorders.

Behavioral and psychological symptoms (BPSD) are now known to be frequently associated to cognitive and functional decline in Alzheimer's disease and related disorders. They are present since the early stages of the disease and have negative impact on the disease process. BPSD assessment is crucial in clinical practice and also in future clinical trials targeting disease-modifying therapies for dementia. In this article, we will first review current assessment tools for BPSD, mainly global and domain-specific scales, and new assessment methods, currently available or in development, including new scales, diagnostic criteria and new technologies such as ambulatory actigraphy.

Importance of lack of interest in patients with mild cognitive impairment.

OBJECTIVE: Apathy is one of the most common behavioral symptoms in mild cognitive impairment (MCI). The aim of the authors' study was to examine the influence of the apathy dimensions, i.e., emotional blunting, lack of initiative, and lack of interest, on the risk of developing of Alzheimer disease (AD) in patients with MCI. DESIGN: Longitudinal study. SETTING: Fourteen French memory clinics. PARTICIPANTS: Apathy was assessed in 214 MCI patients. The main endpoint considered was the development of AD during the 3-year follow-up. MEASUREMENTS: The neuropsychiatric evaluation included the Goldberg anxiety scale and the Montgomery and Asberg Depression Rating Scale; apathy was assessed with the Apathy Inventory. RESULTS: After 3 years, 59 patients (27.2%) had developed AD. The risk of conversion to AD was significantly higher for patients with lack of interest. Using Cox analyses, controlling for age, gender and education, the difference between survival curves was significant for lack of interest. CONCLUSIONS: Lack of interest, a mild behavioral sign, could be an indicator of potential decline in MCI patients and underlines the importance of checking the cognitive status of these patients.