Neuropsychiatric Inventory Apathy 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.

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.

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.

P104: Heterogeneity of Response to methylphenidate in apathetic patients in the ADMET 2 Trial

Background:Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. We assessed response in ADMET 2 to identify individuals likely to benefit from methylphenidate.Methods:In ADMET 2, AD patients with clinically significant apathy were randomized to methylphenidate or placebo. Twenty-three potential predictors of treatment outcome chosen a priori for evaluation were divided into levels (e.g. anxiety present/absent). For each predictor, change in Neuropsychiatric Inventory apathy (NPI-A) due to methylphenidate for each level was estimated. Predictors with larger differences in effect (>= 2pt NPI-A) between levels were selected. Participants were then grouped into 10 subgroups by their index scores, constructed based on model-based prediction of response (NPI-A >=4).Results:In total 177 participants (66% male, mean (SD) age 75.7 (8.0), Mini-Mental State Examination 18.9 (4.8)) had 3 month follow-up data. Six potential predictors met criteria for multivariate modelling. The median Index score was -1.33 (range: -8.35 to 6.83). Methylphenidate was more efficacious in participants with no NPI anxiety (change in NPI-A - 2.21, Standard Error (SE):0.60, p=0.0004) or agitation (-2.63, SE: 0.68, p=0.0002), and who were on cholinesterase inhibitors (ChEI) (-2.44, SE:0.62, p=0.0001), between 52-72 years of age (- 2.93, SE:1.05, p=0.007), had normal diastolic blood pressure (-2.43, SE: 1.03, p=0.02), and more functional impairment (-2.56, SE: 1.16, p=0.03) as measured by the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale. After 3 months of methylphenidate, 79% of participants with a higher index score (>median) responded (>= 4pt NPI-A) and 49% of those with a lower index score responded.Conclusions:Individuals who were less anxious or agitated, younger, on a ChEI, had normal diastolic blood pressure, and with more impaired function were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for apathetic AD participants with lower baseline anxiety and agitation.

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.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. Alzheimer's disease patients with clinically significant apathy. Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial

AbstractBackgroundApathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment.MethodIn this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect.ResultOf the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale.ConclusionIndividuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.

Urinary AD7c-NTP Evaluates Cognition Impairment and Differentially Diagnoses AD and MCI.

The AD7c-NTP is a promising biomarker for AD diagnosis. However, the exact urinary AD7c-NTP concentration to differentiate AD from the mild cognitive impairment (MCI) remains inconclusive. We enrolled 98 and 90 clinical defined AD and MCI patients, respectively, and access their cognition impairment with Neuropsychiatric Inventory (NPI) and Mental State Examination (MMSE) along with their urinary AD7c-NTP. We demonstrated that urinary AD7c-NTP level in sequence from high to low was AD, MCI, and healthy groups (P < .01), and the AD7c-NTP was positively and negatively correlated with the NPI and MMSE scores, respectively. Additionally, AD7c-NTP well-matched NPI subscale scores, including agitation, depression, and apathy (P < .05). Importantly, the optimal cut-off AD7c-NTP level to distinguish the AD and MCI was .94ng/mL (sensitivity 85.71% & specificity 73.91%). Conclusively, urinary AD7c-NTP could be used for cognition impairment evaluation and differentiated diagnosis of AD and MCI.

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

AbstractBackgroundApathy is among the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD). Examining the relationships between apathy and AD pathology is needed to better understand neurobiological mechanisms for therapeutic intervention that could delay disease progression. Research has shown that tau may correlate more closely with cognitive and behavioral manifestations in AD than amyloid. In the current study, we examined the relationship between regional tau burden and longitudinal change in apathy in older adults with mild cognitive impairment (MCI) and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.MethodA total of 319 ADNI participants (233 with MCI; 86 with AD dementia; age: 75.5 ±8.2; 56% female) underwent flortaucipir (FTP) tau positron emission tomography (PET) and clinical assessment with the Neuropsychiatric Inventory (NPI) every 6‐12 months (average follow up= 39.1 months). The NPI Apathy (NPI‐A) score was examined in relation to tau PET signal in four FreeSurfer defined regions of interest implicated in AD and mood regulation: entorhinal cortex (EC), precuneus, inferior temporal cortex and rostral anterior cingulate cortex (rACC). Separate linear mixed models examined the association between NPI‐A (for each study visit) and FTP SUVR in the above regions and their interactions with time as predictors of interest. Age and sex were included as covariates.ResultHigher precuneus, EC and inferior temporal cortex tau were each significantly associated with greater NPI‐A over time (precuneus: ß=0.0273; t=5.01; 95 % CI (0.016, 0.04); p&lt;0.001; EC: ß=0.023; t=5.05; 95 % CI (0.014, 0.032); p&lt;0.001; inferior temporal: ß=.018; t=4.92; 95 % CI (0.011, 0.026); p&lt;0.001. rACC tau was marginally associated with higher NPI‐A over time: ß=.013; t=1.93; 95 % CI (‐0.00, 0.027) p=0.05.ConclusionThese findings suggest that tau burden in brain regions associated with AD, and less so with mood regulation, is associated with increasing apathy over time in individuals with MCI and AD dementia. Further study of emergent apathy in relation to core AD pathology and other neurobiological mechanisms will provide insight into opportunities for interventions that could slow clinical progression and alleviate patient and caregiver burden.

Apathy in Dementia Methylphenidate Trial 2 (ADMET2): Results of a phase III, placebo‐controlled, double‐blind, 6‐month, multi‐center, randomized clinical trial

AbstractBackgroundApathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer’s Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings.MethodsADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months.Results200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups.ConclusionADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD.

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease

Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Ten milligrams of methylphenidate, twice daily, vs matching placebo. The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. ClinicalTrials.gov Identifier: NCT02346201.

Structural Brain Differences Between Cognitively Impaired Patients With and Without Apathy

Since apathy increases in prevalence with severity of dementia pathology, we sought to distinguish concomitant neurodegenerative processes from brain differences associated with apathy in persons with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). We examined relative structural brain differences between case-control matched cognitively impaired patients with and without apathy. Cross-sectional case-control study. Fifty-eight clinical sites in phase 2 of the AD Neuroimaging Initiative across the United States and Canada. The ≥ 55 years of age with MCI or AD dementia and no major neurological disorders aside from suspected incipient AD dementia. Participants with apathy (n=69) were age-, sex-, apolipoprotein E ε4 allele carrier status-, Mini-Mental State Exam score-, and MCI or AD dementia diagnosis-matched to participants without apathy (n=149). The 3-tesla T1-weighted MRI scan and neurocognitive assessments. Using the Neuropsychiatric Inventory apathy domain scores, participants were dichotomized into a with-apathy group (score ≥ 1) and a without-apathy group (score = 0). Cortical thicknesses from 24 a priori regions of interest involved in frontostriatal circuits and frontotemporal association areas. False-discovery rate adjusted within-group comparisons between participants with apathy and participants without apathy showed thinner right medial orbitofrontal (mOFC; meandifference(MD)±standarderrorofMD(SE)=-0.0879±0.0257mm; standardizedMD(d)=-0.4456) and left rostral anterior cingulate (rACC; MD±SE=-0.0905±0.0325mm; d=-0.3574) cortices and thicker left middle temporal cortices (MTC; MD±SE=0.0688±0.0239mm; d=0.3311) in those with apathy. Atrophy of the right mOFC and left rACC and sparing of atrophy in the left MTC are associated with apathy in cognitively impaired persons.

Efficacy and safety of amantadine as a treatment for apathy after brain injury: Two single-case experimental design studies

ABSTRACT Studies on the efficacy of amantadine as a treatment for apathy after brain injury are scarce and of low quality. We examined the efficacy and safety of amantadine for treatment of apathy in two individuals with brain injury. Two double-blind, randomized, single-case experimental (baseline-amantadine-placebo-withdrawal) design (SCED) studies. Apathy measures included a Visual Analogue Scale (VAS), the Neuropsychiatric Inventory (NPI) apathy subscale and the Behavior Rating Inventory of Executive Function for Adults “Initiate” subscale. Safety measures included a rating scale of possible side effects of amantadine and physical examinations. No difference in apathy symptoms (VAS) between baseline and amantadine phase was found in case 1 (NAP = 0.55). Surprisingly, in case 2, apathy symptoms deteriorated from baseline to amantadine phase (NAP = 0.28, 90% CI = −0.69 to −0.20) and improved from amantadine to placebo phase (NAP = 0.92, 90% CI = 0.60–1.00). This improvement was also found on the NPI apathy subscale. Side effects of amantadine were observed in case 2. In this SCED study, amantadine did not improve apathy symptoms in two individuals with brain injury. However, this study shows that side effects of amantadine can occur which lead to a significant decrease in well-being. More high quality studies are required.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments

Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

Relationship between executive dysfunction and neuropsychiatric symptoms and impaired instrumental activities of daily living among patients with very mild Alzheimer's disease.

Patients with Alzheimer's disease (AD) experience a gradual loss in their ability to perform instrumental activities of daily living (IADLs) from the early stage. A better understanding of the possible factors associated with IADL decline is important for the development of effective rehabilitation and support programs for patients with AD. Thus, we examined the relationships between comprehensive cognitive functions and neuropsychiatric symptoms and IADLs in patients with very mild AD. In total, 230 outpatients with probable AD were recruited from the Memory Clinic at Kumamoto University Hospital between May 2007 and October 2016. All patients scored ≥21 points on the Mini-Mental State Examination at the first assessment. Relationships between the subdomains of the Lawton IADL scale and neuropsychological/neuropsychiatric tests were examined by multiple regression analysis. All analyses were performed separately in men and women. In female patients, scores on the Frontal Assessment Battery were significantly associated with telephone use ability, shopping, and ability to handle finances. Apathy scores in the Neuropsychiatric Inventory (NPI) were associated with telephone use ability, housekeeping, responsibility for own medications, and ability to handle finances. NPI agitation scores were associated with food preparation and housekeeping. Geriatric Depression Scale scores were associated with telephone use ability and ability to handle finances. In male patients, only NPI apathy scores were associated with telephone use ability. These results suggest the importance of properly assessing executive function, depression, and apathy at interventions for impaired IADLs among female patients with very mild AD.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool - ERRATUM.

Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. Fifty care homes in England. Residents (N = 726) with dementia. Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (β = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

Neuropsychiatric symptoms in severe dementia: Associations with specific cognitive domains the Cache County Dementia Progression Study.

To examine the prevalence of neuropsychiatric symptoms (NPS) and cognitive correlates in severe dementia. A population-based sample of 56 individuals with severe dementia (85.7% Alzheimer's type; 67.9% female) were assessed with the Severe Cognitive Impairment Profile (SCIP) and the Neuropsychiatric Inventory (NPI). Descriptive statistics displayed the frequency of NPS and bivariate and multiple regression analyses examined the associations between cognitive domains on the SCIP and NPS total, domain, and cluster scores. NPS were common in severe dementia with 98% of the sample exhibiting at least one symptom. Most common were delusions, apathy, agitation/aggression, and aberrant motor behavior, affecting 50% or more of participants. SCIP comportment was significantly associated with NPI total score and apathy (r=-.350 and -.292, respectively). All SCIP domains except for arithmetic, visuospatial, comportment, and motor behavior were significantly associated with agitation/aggression (r=-.285 to -.350). These associations remained in individual multiple regression models. In severe dementia, impairment in specific cognitive domains was associated with more severe NPS. Environmental manipulations to reduce processing demands in persons with severe dementia may be a useful strategy to target agitation and aggressive behaviors.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool.

Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. Fifty care homes in England. Residents (N = 726) with dementia. Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (β = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

Apathy and right caudate perfusion in idiopathic normal pressure hydrocephalus: A case-control study.

Apathy is prevalent in patients with idiopathic normal pressure hydrocephalus (iNPH), a treatable disorder resulting from ventricular enlargement. We assessed the relationship between apathy and regional cerebral blood flow (rCBF) in patients with iNPH. Before lumbo-peritoneal shunt surgery (LPS), 56 iNPH patients were evaluated on apathy and dysphoria subscales of the Neuropsychiatric inventory (NPI), and were divided into two groups according to NPI apathy score: 15 without apathy (iNPH-APA) and 41 with apathy (iNPH+APA). Among iNPH+APA, 29 patients were evaluated for apathy and dysphoria 3months after LPS, and were divided into two groups on the basis of the change in NPI apathy score: 13 with improvement (iNPH+ImpAPA) and 16 without improvement in apathy (iNPH-ImpAPA). N-isopropyl-p-iodoamphetamine single photon emission computed tomography using the autoradiography method was performed before and after LPS, and rCBF was calculated in 22 regions of interest in the frontal cortex, basal ganglia, and limbic system. In iNPH+APA, rCBF in the right caudate nuclei before LPS was significantly lower than that in iNPH-APA (P=0.004; two-sample t test). Between iNPH-ImpAPA and iNPH+ImpAPA, a significant group-by-shunt interaction was observed for rCBF in only the right caudate nuclei (F1, 28 =11.75, P=0.002; two-way repeated-measures analysis of variance), with increased rCBF in iNPH+ImpAPA but not in iNPH-ImpAPA. The significant group-by-shunt interaction persisted if change in NPI dysphoria scores was used as a covariate (F1, 27 =8.33, P=0.008). Our findings suggest that right caudate dysfunction might cause apathy in iNPH patients.

Psychometric Properties of Apathy Scales in Dementia: A Systematic Review.

Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.