Apathy In Alzheimer's Disease Research Articles

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2.

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

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8lb (95% confidence interval, CI: 0.7, 4.9lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Methylphenidate for Apathy in Alzheimer's Disease: Addressing Heterogeneity of Response, Safety Outcomes and Future Directions

Apathy is found in 24-85% patients with Alzheimer's disease (AD), making it the most common neuropsychiatric symptom (NPS) of AD. Apathy in AD is associated with faster disease progression, greater cognitive decline, increased caregiver distress and decreased quality of life, and hence is an important interventional target with no current approved treatments. The recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), the largest randomized, double-blind, placebo-controlled, multi-center, phase III clinical trial that investigated the efficacy of methylphenidate for apathy in patients with mild to moderate AD, found that methylphenidate showed some improvement in apathy. As a dopamine and norepinephrine reuptake inhibitor, methylphenidate increases dopamine and norepinephrine levels, dysfunction of which have been linked to apathy in dementia previously.In this symposium, Dr. Rosenberg will present the safety and efficacy results of the ADMET2 trial with methylphenidate presenting a safe profile with a small to medium effect on apathy. Additional data on cardiovascular safety will be presented and discussed. Dr. Lanctot will speak about the heterogeneity of response in methylphenidate in the trial participants, touching upon clinical characteristics and blood-based biomarkers as predictors of response. Dr. Mintzer will present the rationale and the study design for future trials. Findings from the methylphenidate trial for treatment for apathy in dementia not only shine a light on the pathophysiology of the disease but can also improve knowledge and understanding of potential treatment and research pathways.

The Effect of Apathy and Depressive Syndromes on Functional Outcomes in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. Its initially characterized by progressive short-term memory loss followed by cross-domain cognitive decline in later stages resulting in significant functional deficits and loss of activities of daily living (ADLs) independence. Apathy and depression are frequent neuropsychiatric sequelae in AD, but their contribution to functional deficits is poorly understood. We aimed to quantitatively investigate if apathy and depressive symptoms predict ADLs in AD. We also wanted to fractionate apathy dimensions by factor-analyzing the apathy evaluation scale (AES) and then investigate the dimensions' relation to ADLs. We recruited a sample of 115 patients with probable or possible AD and assessed them for depression, apathy, and ADLs alongside other measures. We hypothesized that apathy and depressive symptoms would predict ADLs and that AES items will load into cognitive, behavioral, and affective factors that would differentially relate to ADLs. Our results indicated that apathy symptoms predict ADLs deficits. The AES items resolved into a three-factor solution but the manner of clustering diverged from that proposed by AES authors. When these factors were regressed simultaneously, only behavioral apathy predicted global ADLs. Distinguishing basic from instrumental ADLs showed that behavioral and cognitive apathy symptoms associate with ADLs deficits while affective symptoms do not. Our results highlight the influence of apathy on ADLs in AD. This has important implications for patient care considering the high prevalence of apathy in AD and other dementing illnesses.

Longitudinal associations of apathy and regional tau in mild cognitive impairment and dementia: Findings from the Alzheimer's Disease Neuroimaging Initiative.

It is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Three hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually. Longitudinal NPI Apathy (NPI-A) scores were examined in relation to baseline tau PET signal in three a priori selected regions implicated in AD and AD-related apathy (supramarginal gyrus, entorhinal cortex [EC] and rostral anterior cingulate cortex [rACC]). Secondary models were adjusted for global cognition (Mini-Mental State Examination score) and cortical amyloid (florbetapir PET). Higher baseline supramarginal gyrus and EC tau burden were each significantly associated with greater NPI-A over time, while rACC tau was associated with higher NPI-A but did not predict its trajectory over time. These results were retained for supramarginal and EC tau after adjusting models for global cognition and cortical amyloid. Our findings suggest that baseline in vivo tau burden in parietal and temporal brain regions affected in AD, and less so in a medial frontal region involved in motivational control, is associated with increasing apathy over time in older adults with MCI and AD dementia. Future work studying emergent apathy in relation to not only core AD pathology but also circuit level dysfunction may provide additional insight into the neurobiology of apathy in AD and opportunities for intervention. Tau (Flortaucipir PET) in regions implicated in AD was associated with increasing apathy over timeCortical amyloid was also found to be a robust predictor of the trajectory of apathyEvidence of synergy between regional tau and amyloid in overall higher levels of apathy.

S12: Recent advances in therapies for late-life neuropsychiatric disorder

Symposium OverviewThis international symposium combining experts from Canada, Australia and the USA and supported by the American Association for Geriatric Psychiatry will present an update on the recent advances in therapeutic interventions for late life mood and cognitive disorders, including late life depression, anxiety and apathy associated with dementia, and preventive strategies including mind-body interventions. Four leaders of the field will present the summary of novel studies: starting with Dr. Benoit Mulsant (CA) presenting the results of the recently completed OPTIMUM study of novel strategies optimizing treatment of late-life treatment resistant depression. He will be followed by Dr. Krista Lanctot’ (CA) update on novel therapies for apathy associated with Alzheimer’s disease, and Dr Nancy Pachana (AU) will present on non-pharmacological approaches to treatment of anxiety associated with neurodegenerative disorders. Finally, Dr. Helen Lavretsky (USA) will present on the recent studies of mind-body therapies used to treat and prevent late life depression and cognitive decline, along with the discussion of the underlying neurobiological mechanisms. The panel will conclude with a brief discussion of future directions in the development of therapeutic interventions.Treatment-resistant depression in late life has been understudied and is lacking evidence supporting augmentation or switching strategies. Recently completed OPTIMUM multi-site study (funded by the PCORI) sought to compare effectiveness of augmentation strategies (bupropion or aripiprazole) to switch to bupropion, in the first step of 1-week acute treatment followed by randomization into the 2nd step of augmentation with Lithium or switch to nortriptyline. The augmentation strategies in the first step produced the most robust response compared to switching, and did not differ in the 2nd step. Primary outcomes included remission rates and wellbeing measures. A discussion of future directions will be provided at the end of this presentation.In those with Alzheimer’s disease, apathy is common and associated with decreased quality of life, increased risk of decline and increased mortality. As such, apathy is increasingly recognized as an important treatment target. Recent advances in diagnosis and treatment will be reviewed.In this presentation, several methodological issues will be discussed, such the importance and prevalence of apathy in Alzheimer’s disease (AD); current diagnostic criteria for apathy in neurocognitive disorders, and will present the results of recent pharmacologic interventions for apathy in AD.In this presentation, new focused and innovative treatments for anxiety in persons with Alzheimer's and Parkinson's disease with co-morbid anxiety will be discussed. Anxiety is common in Alzheimer's Disease and Parkinson's disease and contributes to increased disability and poorer quality of life. Yet only a small fraction of such patients received any form of treatment for mental health issues. Non-pharmacological approaches to address anxiety are advantageous in these populations. Research on tailored CBT and innovations such as virtual reality approaches for these groups will be discussed.Standard pharmacological therapies for treatment of late life depression offer limited efficacy with the downside of adverse events and drug-drug interaction. Novel strategies are needed for more effective and safe treatment and prevention strategies for mood and cognitive disorders in late life. This presentation will focus on the recently completed studies of Tai Chi for treatment of late life depression, and yoga for prevention of cognitive decline in older women at risk for Alzheimer’s disease. Neural and peripheral biomarkers of treatment response will be described. Future directions in mind-body therapies research will be outlined.

P105: Measuring clinically relevant change in apathy symptoms in ADMET 2

Objective:Treatments trials for apathy in Alzheimer’s disease assess change scores on widely used assessment scales. Here, we aimed to determine whether such change scores on the Neuropsychiatric Inventory - Apathy (NPI-A) scale indicate clinically meaningful change.Methods:Participants completing the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) were included. Participants in this randomized trial received methylphenidate or placebo for 6- months along with a psychosocial intervention. Assessments included Clinical Global Impression of Change in apathy (CGIC-A) and the NPI-A. Participants in both groups with complete data at the six-month visit were included. CGIC-A was assessed as improved (minimal, moderate or marked), no change, or worsened (minimal, moderate or marked). For CGIC-A levels, mean and standard deviation (SD) of the change in NPI-A from baseline was calculated. Spearman correlation determined the association between change in NPI-A and CGIC-A, and Mann-Whitney U tests determined differences between the ‘no change’ group and the ‘improved’ and ‘worsened’ groups. Effect size (mean NPI-A difference between either ‘improved’ and ‘no change’/ SD of overall change) were calculated. Differences were also assessed at 3 months as a sensitivity analysis.Results:Overall, 177 participants were included (median age: 77years, Mini Mental State Examination score: 19.3 (4.8), baseline NPI-A [mean, SD]: 7.9, 2.3), change in NPI-A: -3.7 (3.9). On the CGIC-A, 69 were improved, 82 showed no change, and 26 worsened. The Spearman correlation between NPI-A change and CGIC-A was 0.41 (p= 1x 10-8). The change in NPI-A among participants who improved was -5.3 (4.1) [W=1873, p= 3x10-4], among those who worsened was -1.2 (3.1) (W= 1426.5, p= 0.009) compared to those with no change (-3.2 [3.4]),. The NPI-A score for minimal clinical improvement was -4.5 (4.6) with a small effect size of -0.32, which was consistent at 3-months (-0.31).Conclusion:A minimal clinically significant improvement over 3 and 6-months corresponded to a mean decline of 4.5 points on the NPI-A; however, there is considerable overlap in the NPI-A between levels of clinical impression of change.

Blood‐based biomarkers for predicting treatment response in the Apathy in Dementia Methylphenidate Trial 2 randomized clinical trial

AbstractBackgroundThe Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate (MPH) was modestly efficacious is treating apathy in Alzheimer’s disease (AD) with 66% response (> = 4 point decrease on Neuropsychiatric Inventory – apathy (NPI‐A). Here, we evaluated if blood‐based biomarkers potentially associated with treatment‐limiting neuronal damage predicted the probability of treatment response.MethodADMET 2 participants with baseline and endpoint (6 month) NPI‐A and baseline concentrations of (i) neuronal damage: neurofilament light (NFL) and S‐100B, (ii) inflammation: interleukin (IL)‐6, IL‐10, Tumor Necrosis Factor‐alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4‐hydroxynonenal (4‐HNE), 8‐isoprostane (8‐ISO) were included. Biomarkers were normalized by log transformation and pareto scaling. Univariate models examined whether each biomarker interacted with the treatment condition to predict a change of at least 2 points on the NPI‐A. Next, biomarkers with significant associations were included in a multivariate logistical regression model that was used to predict treatment response to MPH and placebo. The index score (difference between response probabilities for MPH and placebo) of each participant indicated their favourability for MPH treatment. Participants were grouped into quartiles by their index score with confidence intervals estimated using non‐parametric bootstrapping.ResultForty‐nine participants (placebo = 26, MPH = 23, age = 75.4 years (standard deviation [SD] = 7.6), 57% males, Mini Mental State Examination = 19.7 [SD = 4.6]) were included. MPH was more efficacious than placebo in those with higher baseline NFL (‐5.8, t = ‐3.1, p = 0.003), and less efficacious in those with higher LPH (2.0, t = 1.48, p = 0.15). Apathy worsened in participants with high TNFα (2.71, t = 1.94, p = 0.06) in both MPH and placebo groups. Participants in the top quartile of the biomarker index score (66.7% on MPH) were more likely to respond to MPH than placebo (index score = 0.58, 95%CI: 0.48, 0.69).ConclusionIndividuals with greater neuronal injury were more likely to respond to MPH, suggesting that MPH supplementation provides more benefit when neuronal injury is more severe. Combining blood biomarkers yielded a prediction score where participants with high NFL and low LPH levels were more likely to respond to MPH. This approach utilizes biomarkers to address heterogeneity in treatment response to MPH.

An Update on Apathy in Alzheimer's Disease.

Apathy is a complex multi-dimensional syndrome that affects up to 70% of individuals with Alzheimer's disease (AD). Whilst many frameworks to define apathy in AD exist, most include loss of motivation or goal-directed behaviour as the central feature. Apathy is associated with significant impact on persons living with AD and their caregivers and is also associated with accelerated cognitive decline across the AD spectrum. Neuroimaging studies have highlighted a key role of fronto-striatial circuitry including the anterior cingulate cortex (ACC), orbito-frontal cortex (OFC) and associated subcortical structures. Importantly, the presence and severity of apathy strongly correlates with AD stage and neuropathological biomarkers of amyloid and tau pathology. Following from neurochemistry studies demonstrating a central role of biogenic amine neurotransmission in apathy syndrome in AD, recent clinical trial data suggest that apathy symptoms may improve following treatment with agents such as methylphenidate-which may have an important role alongside emerging non-pharmacological treatment strategies. Here, we review the diagnostic criteria, rating scales, prevalence, and risk factors for apathy in AD. The underlying neurobiology, neuropsychology and associated neuroimaging findings are reviewed in detail. Finally, we discuss current treatment approaches and strategies aimed at targeting apathy syndrome in AD, highlighting areas for future research and clinical trials in patient cohorts.

Home-based tDCS for apathy in Alzheimer’s disease: a protocol for a randomized double-blinded controlled pilot study

BackgroundApathy is among the most common behavioral symptoms in dementia and is consistently associated with negative outcomes in Alzheimer’s disease (AD). Despite its prevalence and clinical relevance, available pharmacological and non-pharmacological strategies to treat apathy in AD have been marked, respectively, by potentially severe side effects and/or limited efficacy. Transcranial direct current stimulation (tDCS) is a relatively novel non-pharmacological method of neuromodulation with promising results. Compared to previous tDCS formats, recent technological advances have increased the portability of tDCS, which creates the potential for caregiver-administered, home use. Our study aims to evaluate the feasibility, safety, and efficacy of home-based tDCS for the treatment of apathy in AD.Methods/designThis is an experimenter- and participant-blinded, randomized, sham-controlled, parallel-group (1:1 for two groups) pilot clinical trial, involving 40 subjects with AD. After a brief training, caregivers will administer tDCS for participants at home under remote televideo supervision by research staff to ensure the use of proper technique. Participants will be assessed at baseline, during treatment (week 2, week 4, and week 6), and 6 weeks post-treatment. Dependent measures will cover cognitive performance, apathy, and other behavioral symptoms. Data about side effects and acceptability will also be collected.DiscussionOur study will address apathy, an overlooked clinical problem in AD. Our findings will advance the field of non-pharmacological strategies for neuropsychiatric symptoms, presenting a great potential for clinical translation.Trial registrationClinicalTrials.gov, NCT04855643.

The Differential Role of Executive Apathy in Alzheimer's Disease Dementia, Mild Cognitive Impairment and Healthy Cognitive Ageing.

The objective of the present work was to compare the levels of executive, emotional, and initiation apathy in individuals with mild cognitive impairment (MCI), mild Alzheimer's disease dementia (ADD), and cognitively intact healthy controls (HCs). Fifty-two patients with mild ADD, 40 individuals with MCI, and 37 cognitively intact individuals were included in the current study. The participants were consecutive visitors to the Outpatient Memory Clinic of "Nestor" Alzheimer's Center. The symptoms of apathy were measured with the dimensional apathy scale. Analyses showed that ADD patients had significantly higher degrees of executive, emotional, initiation, and overall apathy compared with both the MCI group and the HCs. Additionally, a significant difference was observed in the dimension of executive apathy between individuals with MCI and the HCs. In conclusion, the dimension of executive apathy was the most sensitive measure regarding the differentiation of individuals with mild ADD or MCI and HCs. Hence, detailed evaluation of executive apathy in older individuals referred to a memory clinic may provide useful information contributing to their diagnostic categorization and to the differentiation between neurocognitive disorders and healthy cognitive ageing.

APATHY In Alzheimer's disease: A state of no feeling in the world of fading memories

Apathy is a common neuropsychiatric symptom (NPS) characterized by a loss of motivation, emotional reactivity, and initiative. It is one of the most prevalent, stable, and persistent NPS observed across the neurocognitive disorders (NCD) spectrum. Apathy in NCD is linked to poorer disease outcome, reduced daily functioning, higher levels of caregiver distress, and an increased risk of mortality. Apathy is common in NCD such as Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) and its prevalence increases linearly with disease and time progression. Cross-sectionally, apathy in non-demented groups is associated with executive dysfunction, poorer quality of life, olfactory disturbance, subjective impairments in physical functioning, impairment in instrumental activities of daily living, and greater family caregiver burden. Longitudinally, apathy in non-demented individuals is associated with functional decline, slowed gait and frailty, and incident cognitive decline and dementia. Differentiating points between apathy and depression will be discussed. Building on initial attempts to define and operationalize diagnostic criteria for apathy, an international consensus proposed initial diagnostic criteria for the syndrome apathy to be applied in clinical practice independently of its etiology. Diagnostic criteria of 2008, 2018 and 2021 to be discussed and the revisions to be discussed. Pharmacotherapies include acetylcholinesterase inhibitors, gingko biloba, memantine, and stimulants. Non-pharmacological strategies include multisensory stimulation, music therapy, cognitive stimulation, pet therapy. The threshold of initiating pharmacotherapy is not defined and varies with factors such as excess disability of the patient, potential for improvement in quality of life, distress/burden to caregivers.

Hypothalamic Functional Connectivity and Apathy in People with Alzheimer's Disease and Cognitively Normal Healthy Controls.

Earlier studies have described the neural markers of apathy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-β-verified AD. AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction.

SSRI-associated apathy in Alzheimer's disease: a case series

Apathy is one of the most common manifestations of neurodegenerative pathology, including Alzheimer's disease (AD). Despite such a significant role of apathy in the course of the disease, there are no unambiguous recommendations for the treatment and prevention of this symptom complex. Some classes of psychotropic drugs commonly prescribed for AD, such as antidepressants of the SSRI class, may themselves cause apathy. The authors present a series of clinical observations describing four cases of deterioration in the condition of patients with AD during SSRI therapy. The features of the clinical course of the disease are discussed, new strategies for drug therapy are proposed.

Factors Associated with Apathy in Alzheimer's Disease: A Cross-Sectional Analysis of the Texas Alzheimer's Research and Care Consortium (TARCC) Study.

Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer's disease (AD). To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer's Research and Care Consortium (TARCC) study. This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory-Questionnaire applied to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation.

Methylphenidate and Other Pharmacologic Treatments for Apathy in Alzheimer's Disease.

Apathy is a common and important yet often ignored neuropsychiatric symptom of Alzheimer's disease (AD). Cholinesterase inhibitors and memantine, used to treat AD, appear ineffective against apathy. A meta-analysis of 4 randomized, placebo-controlled trials (RCTs) found that psychostimulants significantly attenuated apathy ratings in AD. However, the pooled sample size in this meta-analysis was just 156, and one of the trials was a 2-week crossover study with a large effect. A large RCT (n = 200) has now been published. This study found that methylphenidate (MPH; 20 mg/d) was superior to placebo in the attenuation of apathy scores in patients with possible or probable, mild to moderate AD; the advantage was evident by the end of the second month of treatment and remained evident to the end of 6 months. The effect size at 6 months was small (Cohen d = 0.37). In this RCT, disappointingly, MPH was not superior to placebo on secondary outcomes, including informant-rated apathy, dependence, activities of daily living, quality of life, and neurocognitive performance; caregiver burden was not formally studied. Speculatively, the psychosocial intervention provided to all participants in this RCT may have boosted response in the placebo group, thereby attenuating differences in outcomes between the MPH and placebo groups. A reasonable conclusion is that whereas MPH may attenuate the severity of apathy in patients with AD across as long as 6 months, the absence of improvements in measures of dependence, activities of daily living, and quality of life suggest that this effect of MPH on apathy may not be clinically significant. An unanswered question is whether the benefits of MPH may be clinically significant in real world practice settings in which the delivery of behavioral interventions is not feasible.

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort.

Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. To identify neuroanatomical correlates of AD-associated apathy. We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

A Drug for Attention-Deficit Disorder Helps Ameliorate Apathy in Alzheimer's Disease

A Drug for Attention-Deficit Disorder Helps Ameliorate Apathy in Alzheimer's Disease

Characterization of apathy-like behaviors and their relationship to Aβ pathology in 5xFAD mice.

Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive cognitive decline and neuropsychiatric symptoms (NPS) with apathy being highly common. The neurobiological mechanisms of apathy in AD are unclear. This study characterized apathy-like behaviors in 5xFAD mice and their relationship to amyloid-beta (Aβ) pathology in the hippocampus and prefrontal cortex (PFC). We examined apathy-like behavior in male and female 5xFAD mice and wild-type controls at 6, 12, and 16 months of age (n=9-14 per group). Behavioral paradigms included nest building, marble burying, and food burrowing, and we calculated apathy composite scores for each mouse from the results of these three tests. Then, we measured soluble Aβ42 in the hippocampus and PFC of the male and female 5xFAD mice with the highest and lowest apathy composites within each age group by ELISA assay. Finally, we characterized Aβ plaque density and size in the hippocampal CA1 subregion and the PFC using thioflavin-S staining and ImageJ. Three-way, independent sample ANOVAs were conducted to determine the effects of age, gender, and genotype or apathy status on behavioral or biochemical outcomes, respectively. Apathy-like behaviors occurred in 5xFAD mice at all ages (p<.0001 at 6, 12, and 16 months), and these behaviors became more prominent with age. Females displayed more apathetic-like behaviors than males (p<.01). Soluble Aβ42 was substantially greater for 16-month than 6-month 5xFAD mice in the hippocampus (p<.0001) and PFC ( p<.001) and for 12-month than 6-month 5xFAD mice in the hippocampus (p<.01). Higher apathy composites were associated with greater soluble Aβ42 in the PFC and more plaques in the CA1 subregion than lower apathy composites (p<.05 for both). In the PFC, female 5xFAD mice had more plaques than males (p<.01). Plaque density in the CA1 subregion and plaque size in the PFC were greater in 12-month compared to 6-month 5xFAD mice (p<.05 for both). This study demonstrates that 5xFAD mice display apathy-like behaviors starting at 6 months that become significantly worse with age and potentially differ between sexes. Additionally, our study suggests correlations between apathy and soluble and insoluble Aβ pathology that differs by brain region.

Cost of illness of apathy in Alzheimer’s disease

AbstractBackgroundWithin a 12‐week multicentre randomised controlled trial, standardised data on resource use of patients and their caregivers was collected using the Resource Utilization in Dementia (RUD) instrument. The aim of this study is to evaluate the insufficiently known influence of apathy on resource utilisation in Alzheimer's patients and their caregivers.Method107 patients were included in the study. Costs were collected from a societal perspective over a four‐week period and examined depending on the Apathy Evaluation Scale‐Clinician Version (AES‐C). Using the Mann‐Whitney U and Kruskal‐Wallis tests, potential cost drivers were identified in a univariate analysis. Afterwards potential cost drivers for total costs, patient costs and caregiver costs were analysed using a generalised linear model (GLM) with a γ‐distributed dependent variable and log link function.ResultThe mean total costs were €3,069. The mean patient costs were €359 and were mainly related to professional services, hospitalisation and medication. The mean caregiver costs were €2,711 and were largely caused by informal care with a share of €2,509. Within the sensitivity analysis, informal care costs decreased to €1,742 and €903, respectively. The multiple regression analysis showed that Apathy, represented by the AES‐C, is a cost driving factor for total costs and caregiver costs, however not for patient costs.ConclusionPrevious studies have often presented costs as a function of cognitive impairment. The present data show that apathy also has a significant influence on resource utilisation. At the same time, however, it was also shown that this influence was mainly caused by the increased resource use of the caregivers and that the resource use of the patients did not show significant changes.