Neuropsychiatric symptoms in mild cognitive impairment: differences by subtype and progression to dementia

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY

Int J Geriatr Psychiatry 2009; 24: 716–722.

Published online 12 January 2009 in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/gps.2187

Neuropsychiatric symptoms in mild cognitive impairment:differences by subtype and progression to dementia

Emily R. Edwards1, Adam P. Spira5*, Deborah E. Barnes1,4 and Kristine Yaffe1,2,3,4

1Department of Psychiatry, University of California, San Francisco, CA, USA2Department of Neurology, University of California, San Francisco, CA, USA3Department of Epidemiology, University of California, San Francisco, CA, USA4San Francisco VA Medical Center, CA, USA5Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

SUMMARY

Background Neuropsychiatric symptoms (NPS) are common in patients with mild cognitive impairment (MCI). Little isknown, however, about how NPS vary by MCI subtype (i.e. amnestic, single domain non-memory, and multiple domain). Inaddition, it is unclear whether NPS increase risk of progression to dementia. We investigated the distribution of NPS acrossMCI subtypes and determined whether NPS increase risk of progression to dementia.Method Participants were 521 patients diagnosed with MCI at the Alzheimer’s Research Centers of California between1988 and 1999. At baseline, patients were classified into MCI subtypes and were assessed for NPS.Results The mean number of NPS was 2.3 (range 0–9.6; 74% had �1 NPS). Patients with �4 NPS had more medicalcomorbidities and greater functional impairment (p� 0.0001 for both). Patients with �4 NPS were more likely than patientswith 0–3 NPS to have amnestic MCI (81% vs 71%, respectively, p¼ 0.03), and patients with amnestic MCI were more likelythan those with other subtypes to exhibit depressive symptoms. Patients with �4 NPS had nearly 2.5 times the odds ofdeveloping dementia at follow-up than patients with 0–3 NPS (adjusted OR¼ 2.44, 95% CI 1.07, 5.55).Conclusion NPS are common in MCI patients. Those with an elevated number of NPS may be more likely to have theamnestic subtype of MCI, and depression may be more common in amnestic MCI than in other subtypes. An elevated numberof NPS may increase risk of progression to dementia for patients with MCI. Copyright # 2009 John Wiley & Sons, Ltd.

key words— mild cognitive impairment; neuropsychiatric symptoms; dementia

Neuropsychiatric symptoms (NPS) such as depression,anxiety, agitation, apathy, hallucinations, and delusionsoften are discussed in the context of the dementias,including Alzheimer disease (AD), vascular dementia,and frontotemporal dementia. NPS occur in 60–80% ofolder adults with dementia (Lyketsos et al., 2000; Assaland Cummings, 2002) and are associated with pooroutcomes, including nursing home placement (Steeleet al., 1990; Yaffe et al., 2002).

Mild cognitive impairment (MCI) refers to an inter-mediate stage between normal cognitive aging anddementia (Petersen et al., 1999). Increasing evidence

*Correspondence to: Dr. A. P. Spira, 624 N. Broadway, HamptonHouse, Rm. 794, Baltimore, MD, 21205, USA.E-mail: [email protected]

Copyright # 2009 John Wiley & Sons, Ltd.

suggests that MCI, like dementia, is a heterogeneouscondition comprised of various subtypes (Nordlundet al., 2005). The amnestic type––characterized bymemory impairment––is the most common, but othersubtypes such as single non-memory and multipledomain, also are prevalent (Petersen et al., 2001;Petersen, 2004).

As in dementia, an emerging literature suggests thatNPS also occur frequently in patients with MCI(Lyketsos et al., 2002; Geda et al., 2004; Hwang et al.,2004). Over 40% of MCI patients exhibit NPS in aone-month period, and 29% experience clinicallysignificant symptoms (Lyketsos et al., 2002). Thedistinct neuropsychological profile and divergentpatterns of cortical atrophy (Whitewell et al., 2007)observed among individuals with different MCI

Received 20 May 2008Accepted 29 October 2008

neuropsychiatric symptoms in mci 717

subtypes suggest that the number and type of NPSmight also differ by subtype. For example, individualswith MCI characterized by executive dysfunctionmight be more likely to demonstrate apathy than thosewith other patterns of cognitive deficits. Little iscurrently known, however, about how the patterns ofspecific NPS differ across the MCI subtypes (Rozziniet al., 2008), or whether the presence of NPS affectslonger-term outcomes in MCI patients, such asprogression to dementia (Sinoff et al., 2003; Steffenset al., 2006; Palmer et al., 2007).

To address these gaps in the literature, we studiedpatients with MCI at 10 Alzheimer’s disease ResearchCenters of California. We tested the hypotheses that:(a) the number and type of NPS would differ by MCIsubtype; and (b) that a high number of NPS at baselinewould be associated with progression to dementia atfollow-up.

METHODS

Participants were patients evaluated at the Alzhei-mer’s Research Centers of California (ARCCs), state-supported memory disorders clinics with sites at theUniversity of California, Davis (two sites), Irvine, LosAngeles, San Diego, and San Francisco (UCSF) (twosites), the University of Southern California (two sites)and Stanford University. Patients enrolled in theARCCs via self-referral or referral from family orphysician. Data were recorded in the ARCCsMinimum Uniform Dataset (MUDS), and stored atUCSF. We reviewed records of patients evaluatedover 11 years (1988–1999). Inclusion criteria were adiagnosis of MCI, a Mini-Mental State Exam(MMSE) (Folstein et al., 1975) score �20, age �50years, and having adequate existing data to determineMCI subtype. The UCSF Committee on HumanResearch approved this study.

Clinical evaluation

Patients at the ARCCs received a comprehensiveevaluation, including physical examination, neurop-sychological testing and a review of medical records.Each patient and an informant were asked standar-dized questions by trained interviewers concerningdemographic information, medical and psychiatrichistory, and family history of dementia. Functionalstatus was determined using the Blessed-Roth DementiaScale (Blessed et al., 1988). As part of the clinicalevaluation, patients or informants were asked whetherthe following NPS were present: hallucinations,delusions, anxiety, depression (report of �2 of eight


symptoms based on Diagnostic and Statistical Manualof Mental Disorders III-R criteria) (APA, 1987)apathy, disinhibition, changes in sleep, and changes inappetite. The criteria for depression did not includechanges in sleep or in appetite. Additional questionsconcerning anger, aggression, and lability wereincluded in the evaluation from 1992 until 1999.

The typical neuropsychological battery to determinecognitive status and MCI subtype included: TrailmakingTest, Parts A and B (Reitan, 1958), Wechsler AdultIntelligence Scale Block Design and Digit Symbolsubtests (Wechsler, 1992), Boston Naming Test(Kaplan et al., 1983) and Category Fluency Test(Morris et al., 1989), Wechsler Memory Scale LogicalMemory and Visual Reproduction subtests (Wechsler,1987, 1997) and the MMSE. Diagnoses were deter-mined by multi-disciplinary conferences that wereattended at each site by neuropsychologists, nurses,neurologists and psychiatrists. To ensure uniformity ofdiagnoses across sites, inter-rater reliability andconsensus conferences were held. ARCC manualsdescribed diagnostic criteria for dementia, amnesticdisorder (according to the DSM III-R and DSM IVcriteria) (APA, 1987, 1994) other cognitive impair-ment not meeting criteria for dementia (CIND), nocognitive impairment, and diagnosis deferred. Wedefined MCI as including diagnoses of amnesticdisorder and CIND.

Based on the baseline neuropsychological evalu-ation, clinicians rated the severity of patients’cognitive impairment (none, mild, moderate, orsevere) in four domains: memory, language, visual-spatial/parietal, and executive. We classified MCIpatients into one of three categories based on thosewith moderate to severe impairment in the memorydomain only (amnestic MCI subtype), moderate tosevere impairment in a single non-memory domain(single, non-memory MCI subtype), or moderate tosevere impairment in two or more domains (multipledomain MCI subtype).

We collected information on progression todementia from follow-up visits. Dementia diagnoseswere determined based on follow-up ARCC evalu-ations, using the ARCC manual for diagnostic criteria,which closely follow DSM diagnostic guidelines.Dementia etiology also was specified (e.g. Alzheimerdisease, vascular dementia, frontal, other, mixed).

Statistical analyses

Analyses were performed using Stata, Version 9.2 SE(StataCorp, College Station, TX). We determined thebaseline characteristics and the number of NPS in the


DOI: 10.1002/gps

718 e. r. edwards ET AL.

patients diagnosed with MCI. Because NPS itemsregarding anger, aggression, and lability were added tothe clinical evaluation beginning in 1992, we proratedNPS scores of participants enrolled prior to 1992. Inorder to make all visits comparable in an NPS sum-mary score, we assumed that the percentage of itemsendorsed would have been similar if the additionalquestions had been asked. For example, a participantwho endorsed 2 (i.e. 25%) of eight symptoms in 1992would be assigned a score of 2.75 (i.e. 25% of 11).

We compared baseline characteristics of those with0–3 NPS and those with �4 NPS (upper quartile of thesample) using Mann–Whitney tests for continuousvariables and chi-square and Fisher’s exact test fordichotomous variables. We then conducted chi-squaretests to determine whether the number of NPS and thedistribution of specific NPS differed by MCI subtype,and performed post-hoc comparisons where appro-priate.

To determine whether NPS predicted progression todementia, we conducted unadjusted and multivariate-adjusted logistic regression analyses with number ofNPS (0–3, �4) as the predictor and progression todementia at follow-up as the outcome. Diagnosticevaluation of the final logistic model identified severalpatients with poor fit and high influence. We excludedthe four with the poorest fit from regression analyses.

Table 1. Characteristics of patients by number of neuropsychiatric s

Characteristic (Mean (�SD) or %) 0–3 NPS (n¼ 38

Age (years) 73.2� 8.4Education (years) 13.0� 4.1Female (%) 51.1Race (%)

White 74.5African-American 7.1Hispanic 12.1Asian 4.5Other 1.8

Income <$10 K (%) 33.7Comorbidities (Current or Past)

Hypertension 38.4Myocardial infarction 11.4Diabetes 12.7Parkinson’s disease 3.2Stroke 11.1

# Comorbidities (0–5) 1.1 (1.0)Alcohol use >1 times/day 3.7Current Smoker 4.1Family Hx Dementia 29.3Mini-Mental State Exam (0–30) 26.4� 2.7Blessed-Roth (0–17) 1.6� 1.6

N¼ 521.*Mann–Whitney tests for continuous variables, chi-square and Fisher


RESULTS

Eleven thousand and seven hundred and twenty-ninepatients were evaluated at the ARCCs between 1988and 1999. Five hundred and twenty-one patients werediagnosed with MCI and met other inclusion criteria.Demographic data are presented in Table 1. Overall,73.9% of all MCI patients or caregivers reported thatpatients had at least one NPS. The mean number ofNPS was 2.3� 2.1 SD (range 0–9.6). The mostfrequently reported NPS were anxiety (39.3%), sleepchanges (35.2%) and depression (34.9%). MCIpatients with �4 NPS had a higher overall numberof medical co-morbidities (1.5� 1.1 vs 1.1� 1.0;p< 0.0001), and a higher Blessed Roth score(2.3� 2.1 vs 1.6� 1.6; p¼ 0.0001), indicating greaterfunctional impairment.

Prevalence of MCI subtypes anddistribution of NPS

Overall, 73.7% of patients were of the amnestic MCIsubtype; 9.6% had single, non-memory MCI, and16.7% had multiple domain MCI. The distribution ofMCI subtypes differed at the trend level, depending onwhether patients had high or low NPS (x2¼ 5.93,p¼ 0.052) (Table 2). Patients with high NPS were

ymptoms

2) �4 NPS (n¼ 139) p-value*

71.7� 10.1 0.2712.8� 4.3 0.37

54.0 0.560.47

76.85.88.07.32.237.9 0.61

45.3 0.168.0 0.2613.7 0.765.0 0.3214.6 0.28

1.5 (1.1) <0.00012.0 0.962.9 0.6126.0 0.50

26.0� 2.7 0.092.3� 2.1 0.0001

’s exact test for dichotomous variables.


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Table 2. Prevalence of particular MCI subtypes among patientswith 0–3 vs �4 neuropsychiatric symptoms

MCI Subtype Number ofNPS

Chi-square P-value

0–3 �4

Amnestic 71.2 80.6 4.62 0.03Single domain, non-memory 11.3 5.0 4.55 0.03Multiple domain 17.5 14.4 0.73 0.39Total 100 100 — —

N¼ 521.MCI¼Mild Cognitive Impairment; NPS¼Neuropsychiatric Symp-toms.Overall x2¼ 5.93, p¼ 0.052.

Table 4. Association between number of neuropsychiatric symp-toms and progression to dementia

Number ofNeuropsychiatricSymptoms

UnadjustedOR (95% CI)

(n¼ 266)

Multivariate-adjusted*OR (95% CI)

(n¼ 238)

0–3 (ref) 1.00 1.00�4 1.88 (1.003, 3.53) 2.44 (1.07, 5.55)

*Adjusted for age, MMSE score, number of co-morbidities, BlessedRoth score, and study site.


more likely than those with low NPS to have amnesticMCI (81% vs 71%, x2¼ 4.62, p¼ 0.03), and were lesslikely to have single non-memory MCI (5% vs 11%;x2¼ 4.55, p¼ 0.03).

The frequency of most specific neuropsychiatricsymptoms did not differ by MCI subtype (see Table 3).However, depression was twice as frequent in patientswith the amnestic MCI subtype (41%) compared withthe single non-memory subtype (20%) (x2¼ 7.97,p¼ 0.005) or the multiple domain subtype (18%)(x2¼ 15.13, p< 0.001).

Prediction of dementia at follow-up

Of the 521 patients, 270 (52%) had a follow-upevaluation (average time to follow-up¼ 1.6� 1.1

Table 3. Proportion (%) of patients with specific neuropsychiatric s

Neuropsychiatric Symptom

Amnestic (n¼ 384) Single, no

Delusions 10.2Hallucinations 5.8Disinhibition 6.0Depression 40.6Anxiety 41.3Lability 15.5Apathy 22.9Aggression 14.7Anger 29.3Sleep changes 33.3Appetite changes 17.8

N¼ 521.*For all NPS, p-value displayed is for overall x2.**p< 0.05 compared with amnestic MCI subtype.


years). Availability of follow-up data did not differby number of NPS at baseline; 51.3% of those with 0–3 NPS vs 53.2% of those with � 4 NPS returned forfollow-up (x2¼ 0.15, p¼ 0.70). Overall, 64.3% of thepatients with 0–3 NPS had dementia at follow-up,compared to 74.3% of the patients with �4 NPS(x2¼ 2.45, p¼ 0.12).

In an unadjusted logistic regression model, partici-pants with � 4 NPS at baseline had an 88% greaterchance of dementia compared with those with 0–3NPS (OR¼ 1.88, 95% CI 1.003–3.53) (Table 4). Afteradjustment for age, MMSE score, number of co-morbidities, Blessed Roth score, and study site, thisassociation increased to a nearly 2.5-fold increase inodds of progression to dementia (OR¼ 2.44, 95% CI1.07–5.55).

We also conducted analyses including the fouroutliers. As would be expected, their inclusion attenuatedassociations and affected significance in unadjusted(OR¼ 1.61, 95% CI 0.88–2.92) and multivariate-

ymptoms in each MCI subtype

MCI Subtype p-value*

n-memory (n¼ 50) Multiple domain (n¼ 87)

8.0 14.1 0.486.0 3.6 0.80

10.0 6.9 0.5120.0** 18.4** <0.00126.0 38.4 0.1114.6 11.5 0.7120.4 15.1 0.2812.0 11.5 0.7818.4 20.7 0.2149.0 36.1 0.0920.8 23.3 0.48


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adjusted (OR¼ 1.85, 95% CI 0.87–3.93) models, butthe direction and general pattern of associationsremained.

DISCUSSION

Our results suggest that NPS are common among MCIpatients. Approximately 75% of MCI patients referredto the California Alzheimer’s Centers experienced atleast one NPS. Patients with an elevated number ofNPS had more medical co-morbidities and lowerfunctional status, and were more likely to be of theamnestic MCI subtype. In addition, patients withamnestic MCI were twice as likely to have depressivesymptoms, compared to patients with the other MCIsubtypes. Of particular interest is our finding thatpatients with an elevated number of NPS at baselinewere almost 2.5 times more likely to have dementia atfollow-up.

Our results are consistent with those of other studiesthat have shown that NPS are common in MCI.Lyketsos et al. (2002) found that among patients withMCI in the community-based Cardiovascular HealthStudy (CHS), 43% had NPS, with 29% being rated asbeing clinically significant. The fact that our samplewas clinically-based and not community-based mayaccount for the higher prevalence observed among ourparticipants. Anxiety, sleep changes, and depressionwere the most frequently reported NPS in our cohortand this is consistent with relative frequencies inprevious studies. Depression, apathy, anxiety, andsleep changes were among the most frequentlyreported in the CHS (Lyketsos et al., 2002). Similarly,other studies have found that frontally mediatedbehaviors (apathy and executive dysfunction) werereported most often (Ready et al., 2003).

Most demographic variables did not differ amongthe NPS groups. For example, we did not find arelationship between race and NPS. Chan et al. (2003)found, however, that non-white MCI patients were atan increased risk for NPS, compared to whites. In thepresent study, participants with �4 NPS alsoexperienced more co-morbid illness than those with0–3 NPS. It is not surprising that burden of illness isrelated to NPS in MCI; patients with a greater numberof medical illnesses might experience symptoms ofdepression or anxiety as a result of stress related to thesymptoms of these comorbidities and their manage-ment. Similarly, those with greater functional impair-ment may be experiencing more NPS as a result oflower function, or vice versa. A study by Feldmanet al. (2004) found that MCI patients with NPS exhibit


greater functional impairment, and NPS have beenassociated with functional impairment in dementiapatients as well (Devanand et al., 1997). We alsoobserved a trend-level association between MMSEand NPS, and this is consistent with prior findings(Feldman et al., 2004). Given that a higher number ofNPS is associated with greater comorbidity, functionalimpairment, and cognitive impairment, it is possiblethat NPS could serve as a marker for overall diseaseseverity and burden in the setting of MCI.

Consistent with our hypothesis that NPS woulddiffer by MCI subtype, patients with elevated NPSwere more likely to have the amnestic MCI subtype,and depressive symptoms were especially commonamong participants with the amnestic subtype. It maybe that those with amnestic MCI are more likely todevelop depressive symptoms, or it may be thatdepression is a risk factor for amnestic MCI. Previousresearch in amnestic MCI patients has shown highprevalence of depressive symptoms, as well asincreased risk for Alzheimer disease (AD) for thosewith depressive symptoms (Modrego et al., 2004).Indeed, depressive symptoms have been shown to be arisk factor for AD in multiple studies (Speck et al.,1995; Devanand et al., 1996; Copeland et al., 2003).

We also hypothesized that those with a highernumber of NPS would be more likely to progress todementia. We found that an elevated number of NPS atbaseline was associated with a greater likelihood ofreceiving a dementia diagnosis at follow-up, even afteradjusting for age, baseline MMSE score, functionalstatus and co-morbidities. Although a surveillancebias might account for this observation if patients withmore NPS are more closely followed than those withfewer NPS, this is unlikely because follow-up wassimilar in our cohort for patients with high and lownumbers of NPS. Our findings beg the question ofwhether treatment of NPS in MCI might delay or evenprevent progression to dementia. Further research isneeded to address this possibility.

Some limitations in our study design warrantconsideration. First, although a clinician administeredthe MUDS questionnaire to ascertain the presence ofNPS, no validated scale such as the NeuropsychiatricInventory (Cummings et al., 1994) was used. Inaddition, a lack of data on the duration of participants’NPS precluded us from investigating whether NPSduration predicted progression to dementia. Further-more, follow-up data was incomplete in the presentstudy, raising the possibility of selection bias. Finally,because patients were seen at university-based referralcenters, results may not be generalizable to patientsseen at clinics without an academic affiliation.


DOI: 10.1002/gps

KEY POINTS

� Patients with more neuropsychiatric symptoms(NPS) were more likely than those with fewerNPS to have the amnestic subtype of mildcognitive impairment (MCI)

� Depressive symptoms were especially commonin patients with the amnestic MCI subtype

� An elevated number of NPS predicted pro-gression from MCI to dementia.


CONCLUSION

In conclusion, our findings suggest that patients withelevated NPS are more likely to have the amnesticsubtype of MCI, and that depressive symptoms areespecially common in patients with amnestic MCI.Our results also indicate that patients with MCI whohave an elevated number of NPS may have more thantwice the odds of progression to dementia than thosewith fewer NPS. Additional studies are needed todetermine the extent to which NPS duration andseverity predict progression from MCI to dementia.

CONFLICT OF INTEREST

None Known.

ACKNOWLEDGEMENTS

Supported by ADRCC grant 03-75271 from the Cali-fornia Department of Health Services, and by NIHgrants K24 AG031155, and 5 T32 AG000212-15.

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Neuropsychiatric symptoms in mild cognitive impairment: differences by subtype and progression to dementia