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. Author manuscript; available in PMC: 2015 Feb 1.
Published in final edited form as: Int Psychogeriatr. 2013 Oct 29;26(2):239–246. doi: 10.1017/S1041610213001762

Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo controlled trial

Krista L Lanctôt 1, Sarah A Chau 1, Nathan Herrmann 1, Lea T Drye 2, Paul B Rosenberg 3, Roberta W Scherer 2, Sandra E Black 1, Vijay Vaidya 2, David L Bachman 4,5, Jacobo E Mintzer 4,5, for the ADMET investigators
PMCID: PMC3927455  NIHMSID: NIHMS548138  PMID: 24169147

Abstract

Background

Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer’s disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses.

Methods

MPH (10mg PO twice daily) or placebo was administered for 6 weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory [NPI] Apathy≥4). Attention was measured with the Wechsler Adult Intelligence Scale - Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ {[MPH (DS week 6–DS baseline)] - [placebo (DS week 6–DS baseline)]}.

Results

In 60 patients (37 females, age=76±8, Mini-Mental State Exam [MMSE]=20±5, NPI Apathy=7±2), the change in DS forward (δ=0.87 (95% CI: 0.06–1.68), p=0.03) and DS total (δ=1.01 (95% CI: 0.09–1.93), p=0.03) favoured MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder or non-responder groups. DS scores did not predict apathy response to MPH treatment.

Conclusion

These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.

ClinicalTrials.gov Identifier

NCT01117181

Keywords: Alzheimer’s disease, apathy, neuropharmacology, psychopharmacology, behavioral and psychological symptoms of dementia (BPSD)

Background

Alzheimer’s disease (AD) is characterized by cognitive impairment including deficits in measures of attention (McGuinness et al., 2010). Attention deficits emerge during the early stages of dementia (Perry et al., 2000) and may predict increased deterioration and progression to AD in mild cognitively impaired elderly (Rapp and Reischies, 2005). Attention has recently become of interest as a cognitive domain as it has been shown to be specifically associated with executive dysfunction (Perry and Hodges, 1999) and decline in activities of daily living (Bronnick et al., 2006) in AD patients.

Psychostimulants, which work by increasing central dopamine (DA) and norepinephrine levels, are known to enhance alertness, reward salience and motivation (Koob, 1996) and are the standard treatment for attention-deficit hyperactive disorder. The psychostimulant methylphenidate (MPH) has also been shown to significantly improve attention deficits in other DAergic disorders such as Parkinson’s disease (Auriel et al., 2006). Herrmann et al (2008) found that increased inattention following a single dose of dextro-amphetamine predicted greater improvements in apathy (ρ = −0.69, p = 0.02) in AD patients being treated with methylphenidate. The authors proposed that lack of attention may be a predictor of treatment response to MPH, which is consistent with literature in normal controls suggesting that the effects of MPH vary depending on baseline dopamine levels (Cools et al., 2009). However, the study by Herrmann et al (2008) did not assess attention as an outcome.

While attention is a distinct cognitive domain, it may also be associated with apathy. Links between apathy and attention are rational considering that DAergic neurons make projections to attention networks in the brain and attention-associated areas show reduced activity in apathetic patients (Lanctôt et al., 2007). Motivation, identified as one of the key deficits in apathy, is thought to be closely associated with attentional components in reward processing (Ivanov et al., 2012; Nieoullon and Coquerel, 2003). Despite a theoretical common neurobiology, little is known about the relationship between apathy and attention in AD.

A recent randomized placebo-controlled trial (ADMET) suggested that MPH was well tolerated and had positive effects on apathy, with a trend for increases in global cognition (Rosenberg et al., 2013). In this secondary analysis, we investigated the effect of MPH on attention in patients with apathy, as well as the relationship between attention and apathy changes following MPH treatment.

Methods

Study Sample

Patients enrolled in ADMET (Rosenberg et al.) at Sunnybrook Health Sciences Centre, Johns Hopkins University and the Medical University of South Carolina were used in this pre-planned secondary analysis. All study sites received approval from their individual research ethics board. ADMET was a phase II, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of MPH (10mg PO twice daily) versus placebo for 6 weeks for the treatment of apathy in AD patients. Patients were recruited from outpatient clinics, assisted living facilities affiliated with the clinics, referrals from local physicians and advertisements in local media.

Procedures

The study methods have been described elsewhere (Drye et al., 2013). Informed consent was provided by study participants or a legally authorized representative before the start of the trial. Eligible patients with mild-to-moderate AD (Mini-Mental Status Examination, MMSE 10–26 inclusive) and clinically significant apathy (Neuropsychiatric Inventory, NPI Apathy ≥ 4) were randomized, with a 1:1 assignment ratio, to either MPH or placebo for 6 weeks. ADMET allowed use of stable doses of cognitive enhancers, selective-serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors as well as trazodone for sleep, but not treatment with other psychotropic medications. Study drugs (either MPH or placebo) were initiated at 5 mg PO twice daily, for 3 days. This was increased to the target dose of 10 mg PO twice daily (total of 20 mg per day) for the remainder of the trial.

Assessments were performed every 2 weeks (baseline, week 2, week 4 and week 6). Patients completed the Wechsler Adult Intelligence Scale Revised - Digit Span (DS) (Wheeler, 1981), MMSE (Folstein et al., 1975) and modified AD Cooperative Study-Global Clinical Impression of Change (ADCS-CGIC) (Schneider et al., 1997). Caregivers provided information for the patient regarding the eligibility criteria, medical history, NPI (Cummings et al., 1994), Apathy Evaluation Scale (AES) (Marin et al., 1991) and CGIC (Schneider et al., 1997). Vital signs, electrolyte panels and ECG tests were also obtained from patients and adverse events solicited at each study visit to monitor safety throughout the trial. Procedures for test administration were standardized across all study sites.

For this pre-planned secondary analysis of the ADMET study, the DS (Wheeler, 1981) was used to assess auditory attention and working memory. Digit sequences of progressively increasing length were read by the examiner and patients were instructed to repeat them in the same order for the forward condition. In the backward condition, patients were required to repeat the digits in the reverse order. One point was given for each correct sequence and the test was terminated when patients were unsuccessful on two trials of the same sequence length. Performance was summarized by DS forward (selective attention), DS backward (working memory) and DS total scores. Additionally, a scaled score based on standardized age norms was converted from the raw total score.

Statistical Analysis

Baseline clinical and demographic characteristics were compared between response groups using Kruskal-Wallis test for continuous variables and chi-square or Fisher’s exact test for categorical variables. All analyses of treatment effects were conducted according to the intention to treat principle. The treatment effect of MPH [δ] on attention measures compared the difference in change in DS measures from baseline to week 6 between MPH and placebo. This was assessed using linear mixed effects models with random intercept for each participant and adjusting for stratification by clinic. Specifically, differences between MPH compared with PLB for changes from baseline were examined. Cohen’s d (the difference between two means divided by the pooled standard deviation) was calculated for the crude difference in digit span forward change scores.

Apathy responders were those patients who had an improvement of at least 3.3 points on the AES from baseline to end point based on the difference observed in the published pilot study (Herrmann et al., 2008) and power calculations for ADMET (Drye et al., 2013). The relationship between baseline attention measures and treatment response was assessed by: i) linear regression models of the change in AES score from baseline to week 6; ii) logistic regression models of apathy response. We also considered models of the association between attention and apathy response that controlled for education and explored response defined as a decrease in NPI apathy score by 1 point or more at week 6 and response defined as any improvement at CGIC scale from baseline (minimal, moderate, and marked improvement). Pearson correlation and 95% confidence intervals were calculated for change in attention measures (DS total, forward and backward) from baseline to week 6 versus change in apathy measures (AES) from baseline to week 6 for study completers.

Two sided p-value at 5% significance level were used to assess statistical significance. Results were not adjusted for multiple comparisons. Statistical analyses were used using SAS version 9.3 Copyright (c) 2002–2010 by SAS Institute Inc., Cary, NC, USA.

Results

Sixty AD patients (37 women), with a mean ± SD age of 76 ± 8, MMSE scores of 20 ± 5, NPI total scores of 16 ± 8, NPI apathy scores of 7 ± 2 and AES scores of 51 ± 12 were randomized. The patients in each treatment arm (29 in the MPH group and 31 in the placebo group) were comparable on baseline characteristics (Rosenberg et al., 2013). While the number of participants taking ChEls or SSRIs at baseline (Table 1) was balanced by treatment group, memantine use was slightly imbalanced (MPH 21/29, placebo 16/31)(Rosenberg et al., 2013).

Table 1.

Baseline characteristics by responders in the AES

Baseline Characteristics Total (n=57) Responders (n=17) Non-responders (n=40) P-value
Age 77±8 76±10 77±7 0.79
Gender 60% female 53% female 63% female 0.50
Concomitant Medication
 SSRIs 32% 29% 33% 0.81
 ChEIs 72% 71% 72% 0.88
 Memantine 61% 65% 60% 0.77
MMSE 20±5 20±5 20±5 0.79
AES 51±12 55±11 49±12 0.06
NPI Total 16±8 18±9 15±7 0.38
 Apathy subscore 7±2 8±2 7±2 0.73
 Depression subscore 1±2 2±3 1±2 0.14
Digit Span
 Forward score 8±2 8±3 8±2 0.55
 Backward score 4±2 4±2 4±2 0.90
 Total raw score 12±4 12±4 12±4 0.90
 Total scaled score 8±3 8±3 8±3 0.75
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AES=Apathy Evaluation Scale, SSRIs=serotonin reuptake inhibitor, ChEI=cholinesterase inhibitor, MMSE=Mini-Mental Status Exam, NPI=Neuropsychiatric Inventory. Values indicate mean ± SD. Adjusted for unequal variances as needed.

Estimated difference in change in attention for the 60 patients from baseline to week 6 showed larger improvements (positive δ favors MPH) in DS forward score (δ = 0.87 (95% CIs: 0.06–1.68), p=0.03, Cohen’s d = 0.62) (Figure 1) and DS total score (δ = 1.01 (95% CIs: 0.09–1.93), p=0.03) in those on MPH. The difference in improvement was not statistically significant for DS backward (δ = 0.17 (95% CIs: −0.66, 1.02), p=0.68) though it showed a numerically greater improvement in the MPH group. Controlling for use of memantine did not change treatment effects on DS forward scores (δ = 0.87 (95% CIs: 0.06–1.68), p=0.03).

Figure 1.

Figure 1

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Estimated change score (±SE) for Digit Span forward over time. Improvement (positive change scores) over 6 weeks in the MPH (methylphenidate) group (n=29) was significantly greater than that found in the PLB (placebo) group (n=31).

Of the 60 randomized, 57 participants completed the study with 17 patients showing improved apathy and 40 who did not improve (Table 1). Responders and non-responders were comparable on baseline measurements of attention except that responders had a trend towards higher baseline AES scores (p = 0.06). There were no significant correlations between change in AES and change in any of the attention measures for the 57 completers, the MPH group or the PLB group (data not shown). Baseline attention scores did not predict apathy outcome as measured by linear regression model (group differences in change scores) or logistic regression (log odds of improvement in MPH and placebo group by baseline score) (Tables 2 and 3). Controlling for education did not substantially change the size of the association between response and baseline attention. Sensitivity analysis with response using NPI apathy and CGIC apathy also showed no relationship (data not shown).

Table 2.

Linear slope of AES change scores by baseline attention scores and treatment group. Negative difference in slopes (MPH-PLB) favours MPH.

Predictors MPH slope PLB slope MPH - PLB
B (95% CI) P-value B (95% CI) P-value B (95% CI) P-value
DS forward 0.9 (−0.4, 2.1) 0.16 −0.3 (−1.8, 1.2) 0.69 1.2 (−0.8, 3.1) 0.23
DS backward 0.1 (−1.1, 1.4) 0.82 0 (−1.3, 1.4) 0.95 0.1 (−1.7, 2.0) 0.91
DS scaled total 0.3 (−0.6, 1.3) 0.47 −0.2 (−1.3, 0.9) 0.72 0.5 (−0.9, 2.0) 0.46
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Abbreviations: MPH=methylphenidate, PLB=placebo, DS=digit span

*

p<0.05 significance

Table 3.

Odds ratios for baseline attention as predictors of AES response based on logistic regression.

Predictors MPH PLB
OR (95% CI) P-value OR (95% CI) P-value
DS forward 0.8 (0.5–1.1) 0.18 1.5 (0.9–2.5) 0.11
DS backward 0.8 (0.6–1.2) 0.38 1.2 (0.8–1.9) 0.30
DS total scaled 0.8 (0.6–1.1) 0.23 1.3 (0.9–1.9) 0.12
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Abbreviations: MPH=methylphenidate, DS=digit span, PLB=placebo

*

p<0.05 significance

Conclusion

The results of this study suggest that MPH improves selective attention in an elderly dementia population with apathy. While sustained attention or vigilance refers to the ability to maintain focus over long periods of time and divided attention is required to process multiple stimuli simultaneously, selective attention is defined as focus and concentration on a target stimulus while filtering out distractions (Perry and Hodges, 1999). Previous randomized placebo controlled trials with galantamine, a cholinesterase inhibitor that modulates nicotinic receptors, showed positive effects on different measures of attention, including both vigilance and selective attention (Galvin et al., 2008; Gorus et al., 2007; Vellas et al., 2005). While there is evidence for the use of psychostimulants such as MPH for the treatment of apathy in AD (Herrmann et al., 2008; Rosenberg et al., 2013) data on their effects on attention in this population are limited. In children and young adults with ADHD, psychostimulants have been shown to improve performance on tasks of divided, sustained, focused and selective attention (Tucha et al., 2006). Our findings indicate that improvements on selective attention did favour MPH in apathetic dementia patients following 6 weeks of treatment. Further, the estimated change in DS forward found in this study (δ = 0.87) is greater than the difference found between those with mild versus moderate cognitive impairment in the ADNI study (0.7) (Park et al., 2012), and demonstrates a moderate to high effect size (0.62), suggesting that MPH may have clinically significant effects on attention.

The correlation and response prediction analyses also suggest that attention and apathy may respond independently to MPH in this cohort of patients. There are several possible reasons for this. The neural substrates for apathy, thought be to the anterior cingulate and orbitofrontal cortex (Lanctôt et al., 2007), are likely not directly involved in all types of attention processing. It may be that the selective attention test used in this study measured a component of attention that is not closely associated with anterior cingulate or orbitofrontal mediated motivation. Second, differing sensitivity to MPH may account for these differences. Low and therapeutically relevant doses of psychostimulants are cognitively enhancing via preferential stimulation of the prefrontal cortex (Berridge and Devilbiss, 2011). In contrast, higher doses, by amplifying catecholaminergic tone more globally throughout the brain, are behaviourally activating (Kuczenski et al., 1995). In the dementia population, the presence of irritability, agitation and psychosis reported in trials of patients treated with MPH (Galynker et al., 1997; Herrmann et al., 2008; Padala et al., 2010) could signify behavioural effects in a subset of patients even at low doses. This is also consistent with the previous suggestion that the effects of dopaminergic agents depends on baseline dopaminergic activity (Cools and D’Esposito, 2011).

The differing responses may also indicate regional variability in dopaminergic disruption associated with AD. Post-mortem brains of AD patients show lower levels of dopamine (Storga et al., 1996) and D2 receptor expression (Cross et al., 1984) compared with age-matched controls, but the extent of this disruption varies substantially. Consistent with this variability, the DAergic mesocorticolimbic reward pathway is thought to be compromised in AD patients to a greater degree in those with apathy compared to those without (Mitchell et al., 2010). In a SPECT study of non-depressed AD patients, those with apathy had a distinct pattern of differences in areas associated with the DAergic mesocorticolimbic reward pathway (Lanctôt et al., 2007). Reduced striatal DA transporter uptake has also been correlated with greater apathy in dementia patients (David et al., 2008). A probe of the DA reward system demonstrated that compared with controls, apathetic AD patients given d-amphetamine scored lower on tests of subjective positive effects (Lanctôt et al., 2008), possibly representing either loss or decreased sensitivity of post-synaptic DAergic receptors. As such, DAergic dysfunction is likely to be present and variable in an AD population with apathy and may be a factor in driving MPH to have independent effects on apathy and attention.

These results contrast with findings of a drug challenge study (Herrmann et al., 2008), where inattention with d-amphetamine was predictive of a positive response to MPH for apathy. Conceptual differences, including the use of a different psychostimulant, may account for the contradictory findings. The purpose of the drug challenge was to probe the functional integrity of the DA reward system using a single dose of d-amphetamine rather than testing whether MPH-naive attention abilities could predict response. In fact, the authors suggested that the behaviourally activating mechanisms which caused distractibility and subsequently inattention, might also be involved in ameliorating apathetic symptoms. This is consistent with the interpretation of the results discussed above.

There are some limitations to consider when interpreting the results of this study. The sample size was based on power calculations performed to evaluate efficacy of MPH (Drye et al., 2013) with apathy and not attention as the primary outcome. While this study had sufficient power to detect changes in attention, the sample size may not have been adequate to detect significant associations between our two outcome measures. The definition of a responder was based on a previous pilot study and thus far has not been validated. Nevertheless, results from ADMET indicated that clinicians’ impression of change in apathy, measured by the CGIC, favoured MPH, suggesting that a 3.3 point change on the AES was large enough to be clinically relevant. Another limitation is the use of a single measure of selective attention. The Digit Span test, a measure of selective attention (DS forward) and working memory (DS backward), may not be tapping into the attention domains which might be more relevant to the motivation factor characteristic of apathy. While its short length and ease of administration is a benefit in studies with cognitively impaired patients, it would be interesting to explore more comprehensive assessments which target other types of attention. Similarly, activities of daily living, which have been linked with both attention and apathy (Bronnick et al., 2006; McPherson et al., 2002), were not measured in the present study. Finally, given the exploratory nature of this secondary analysis, adjustment was not made for multiple comparisons.

In addition to positive benefits for apathy, as demonstrated by NPI apathy score and modified ADCS-CGIC, as well as a trend for global cognition, as measured by the MMSE recently reported for MPH (Rosenberg et al., 2013), this analysis provides an initial signal supporting benefits on attention, suggesting multiple avenues for future research. For example, since these patient all exhibited apathy, methylphenidate could be studied in non-apathetic patients, specifically as a cognitive enhancer. Also, in this study MPH was given as an adjunctive therapy, thus its use as a monotherapy could be explored. Similarly, MPH was administered for 6 weeks and therefore the effects of long-term use are an important focus for future research, particularly in light of the fact that AD is neurodegenerative and evidence of tolerance in other populations (Swanson et al., 1999). Given that an impact on activities of daily living is important in establishing clinical relevance, future studies should evaluate whether MPH administration improves function. Finally, these results apply only to those patients with mild-to-moderate AD and it would be interesting to investigate patients with more severe AD and non-AD dementias, where the link between DA and attention have yet to be clarified. These data will be particularly important to better define the therapeutic role of MPH in clinical practice.

In summary, the benefit for selective attention found in this study, in addition to previously noted benefits for apathy, adds to the limited knowledge of MPH effects on AD patients and provides further support for its use in this population. Heterogeneity in response to treatment has prompted recent recognition of the importance of evaluating specific cognitive domains (Hendrix and Welsh-Bohmer, 2013). Attention is needed for working and episodic memory, and may also have positive effects on functional abilities (Baddeley et al., 1986; Perry and Hodges, 1999). This study provides some insight into the different effects MPH can produce in a heterogeneous disease such as AD.

Acknowledgments

The authors would like to thank Corinne Fisher (St Michaels Hospital, Toronto) and Nicolaas Paul NG Verhoeff (Baycrest Hospital, Toronto).

Footnotes

Conflicts of Interest: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf and declare that (1) authors KLL, SC, NH, LTD, PBR, RWS, SEB, VV, DLB have no relationships with any companies that might have an interest in the submitted work in the previous 3 years; (2) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) have no non-financial interests that may be relevant to the submitted work. Author JEM, has relationships with NIA that might have an interest in the submitted work in the previous 3 years; (2) his spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) JEM has no non-financial interests that may be relevant to the submitted work.

Description of Authors’ Roles: All authors contributed to the study design, data collection, data interpretation and review of the manuscript. KL Lanctôt and S Chau drafted the manuscript. LT Drye and V Vaidya performed the data analyses for this study. All authors had full access to the data for the study and take responsibility for the integrity of the data and accuracy of the analysis.

References

  1. Auriel E, Hausdorff JM, Herman T, Simon ES, Giladi N. Effects of methylphenidate on cognitive function and gait in patients with Parkinson’s disease: a pilot study. Clin Neuropharmacol. 2006;29:15–17. doi: 10.1097/00002826-200601000-00005. [DOI] [PubMed] [Google Scholar]
  2. Baddeley AD, Logie R, Bressi S, Della Sala S, Spinnler H. Dementia and working memory. Quarterly Journal of Experimental Psychology. 1986;38:603–618. doi: 10.1080/14640748608401616. [DOI] [PubMed] [Google Scholar]
  3. Berridge CW, Devilbiss DM. Psychostimulants as Cognitive Enhancers: The Prefrontal Cortex, Catecholamines, and Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry. 2011;69:e101–111. doi: 10.1016/j.biopsych.2010.06.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bronnick K, et al. Attentional deficits affect activities of daily living in dementia-associated with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2006;77:1136–1142. doi: 10.1136/jnnp.2006.093146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cools R, D’Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011;69:e113–125. doi: 10.1016/j.biopsych.2011.03.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D’Esposito M. Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci. 2009;29:1538–1543. doi: 10.1523/JNEUROSCI.4467-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Markakis D. Striatal dopamine receptors in Alzheimer-type dementia. Neurosci Lett. 1984;52:1–6. doi: 10.1016/0304-3940(84)90341-0. [DOI] [PubMed] [Google Scholar]
  8. Cummings JL, Mega MS, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. Neuropsychiatric Inventory: Comprehensive Assessment of Psychopathaology in Dementia. Neurology. 1994;44:2308–2314. doi: 10.1212/wnl.44.12.2308. [DOI] [PubMed] [Google Scholar]
  9. David R, et al. Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases A SPECT study with partial volume effect correction. Clin Neurol Neurosurg. 2008;110:19–24. doi: 10.1016/j.clineuro.2007.08.007. [DOI] [PubMed] [Google Scholar]
  10. Drye LT, et al. Designing a Trial to Evaluate Potential Treatments for Apathy in Dementia: The Apathy in Dementia Methylphenidate Trial (ADMET) Am J Geriatr Psychiatry. 2013;21:549–559. doi: 10.1016/j.jagp.2012.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198. doi: 10.1016/0022-3956(75)90026-6. [DOI] [PubMed] [Google Scholar]
  12. Galvin JE, et al. Effects of galantamine on measures of attention: results from 2 clinical trials in Alzheimer disease patients with comparisons to donepezil. Alzheimer Dis Assoc Disord. 2008;22:30–38. doi: 10.1097/WAD.0b013e3181630b81. [DOI] [PubMed] [Google Scholar]
  13. Galynker I, Ieronimo C, Miner C, Rosenblum J, Vilkas N, Rosenthan R. Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci. 1997;9:231–239. doi: 10.1176/jnp.9.2.231. [DOI] [PubMed] [Google Scholar]
  14. Gorus E, Lambert M, De Raedt R, Mets T. The influence of galantamine on reaction time, attention processes, and performance variability in elderly Alzheimer patients. J Clin Psychopharmacol. 2007;27:182–187. doi: 10.1097/JCP.0b013e318032eadb. [DOI] [PubMed] [Google Scholar]
  15. Hendrix SB, Welsh-Bohmer KA. Separation of cognitive domains to improve prediction of progression from mild cognitive impairment to Alzheimer’s disease. Alzheimer’s Research & Therapy. 2013;5:22. doi: 10.1186/alzrt176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herrmann N, et al. Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol. 2008;28:296–301. doi: 10.1097/JCP.0b013e318172b479. [DOI] [PubMed] [Google Scholar]
  17. Ivanov I, et al. Effects of motivation on reward and attentional networks: an fMRI study. Brain Behav. 2012;2:741–753. doi: 10.1002/brb3.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Koob GF. Hedonic valence, dopamine and motivation. Mol Psychiatry. 1996;1:186–189. [PubMed] [Google Scholar]
  19. Kuczenski R, Segal DS, Cho AK, Melega W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methylphenidate. J Neurosci. 1995;15:1308–1317. doi: 10.1523/JNEUROSCI.15-02-01308.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lanctôt KL, et al. Apathy associated with Alzheimer disease: use of dextroamphetamine challenge. Am J Geriatr Psychiatry. 2008;16:551–557. doi: 10.1097/JGP.0b013e318170a6d1. [DOI] [PubMed] [Google Scholar]
  21. Lanctôt KL, et al. A SPECT study of apathy in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;24:65–72. doi: 10.1159/000103633. [DOI] [PubMed] [Google Scholar]
  22. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991;38:143–162. doi: 10.1016/0165-1781(91)90040-v. [DOI] [PubMed] [Google Scholar]
  23. McGuinness B, Barrett SL, Craig D, Lawson J, Passmore AP. Attention deficits in Alzheimer’s disease and vascular dementia. J Neurol Neurosurg Psychiatry. 2010;81:157–159. doi: 10.1136/jnnp.2008.164483. [DOI] [PubMed] [Google Scholar]
  24. McPherson S, Fairbanks L, Tiken S, Cummings JL, Back-Madruga C. Apathy and executive function in Alzheimer’s disease. J Int Neuropsychol Soc. 2002;8:373–381. doi: 10.1017/s1355617702813182. [DOI] [PubMed] [Google Scholar]
  25. Mitchell RA, Herrmann N, Lanctôt KL. The Role of Dopamine in Symptoms and Treatment of Apathy in Alzheimer’s Disease. CNS Neurosci Ther. 2010;17:411–427. doi: 10.1111/j.1755-5949.2010.00161.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nieoullon A, Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol. 2003;16(Suppl 2):S3–9. [PubMed] [Google Scholar]
  27. Padala PR, et al. Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am J Geriatr Psychiatry. 2010;18:371–374. doi: 10.1097/JGP.0b013e3181cabcf6. [DOI] [PubMed] [Google Scholar]
  28. Park LQ, et al. Confirmatory factor analysis of the ADNI Neuropsychological Battery. Brain Imaging Behav. 2012;6:528–539. doi: 10.1007/s11682-012-9190-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer’s disease. A critical review. Brain. 1999;122 ( Pt 3):383–404. doi: 10.1093/brain/122.3.383. [DOI] [PubMed] [Google Scholar]
  30. Perry RJ, Watson P, Hodges JR. The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: relationship to episodic and semantic memory impairment. Neuropsychologia. 2000;38:252–271. doi: 10.1016/s0028-3932(99)00079-2. [DOI] [PubMed] [Google Scholar]
  31. Rapp MA, Reischies FM. Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE) Am J Geriatr Psychiatry. 2005;13:134–141. doi: 10.1176/appi.ajgp.13.2.134. [DOI] [PubMed] [Google Scholar]
  32. Rosenberg PB, et al. Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: A randomized, placebo-controlled trial. J Clin Psychiatry. 2013;74:810–816. doi: 10.4088/JCP.12m08099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schneider LS, et al. Validity and reliability of the Alzheimer’s Disease Cooperative Study - Clinical Global Impression of Change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11:S22–32. doi: 10.1097/00002093-199700112-00004. [DOI] [PubMed] [Google Scholar]
  34. Storga D, Vrecko K, Birkmayer JG, Reibnegger G. Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients. Neurosci Lett. 1996;203:29–32. doi: 10.1016/0304-3940(95)12256-7. [DOI] [PubMed] [Google Scholar]
  35. Swanson J, et al. Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin Pharmacol Ther. 1999;66:295–305. doi: 10.1016/S0009-9236(99)70038-X. [DOI] [PubMed] [Google Scholar]
  36. Tucha O, Mecklinger L, Laufkotter R, Klein HE, Walitza S, Lange KW. Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder. J Neural Transm. 2006;113:1575–1592. doi: 10.1007/s00702-005-0437-7. [DOI] [PubMed] [Google Scholar]
  37. Vellas B, et al. Early onset effects of galantamine treatment on attention in patients with Alzheimer’s disease. Curr Med Res Opin. 2005;21:1423–1429. doi: 10.1185/030079905X61884. [DOI] [PubMed] [Google Scholar]
  38. Wheeler D. Wechsler Adult Intelligence Scale - Revised, Manual. New York: Psychological Corporation; 1981. [Google Scholar]

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