Do subjective memory complaints herald the onset of mild cognitive impairment in Parkinson disease?

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Research Investigation

Do Subjective Memory Complaints Heraldthe Onset of Mild Cognitive Impairmentin Parkinson Disease?

RobertoAQ1 Erro1, Gabriella Santangelo2,3, Paolo Barone4, Marina Picillo5,Marianna Amboni3, Katia Longo3, Flavio Giordano4, Marcello Moccia5,Roberto Allocca5, Maria Teresa Pellecchia4, and Carmine Vitale3,6

Abstract

Background: Longitudinal studies on healthy participants have shown that subjective memory impairment (defined as subjectivecognitive complaints with normal cognitive objective performance) might be a strong predictor of mild cognitive impairment(MCI). Parkinson disease (PD) also manifests cognitive disturbances, but whether subjective memory complaints may predict thedevelopment of MCI in PD has not yet been explored. Methods: We prospectively screened newly diagnosed, untreated patientswithAQ2 PD in order to evaluate whether subjective memory complaints may predict development of MCI over a 2-year follow-upevaluation. Results: We enrolled 76 de novo untreated patients with PD. Of the 76 patients, 23 (30.3%) complained memoryissues. Among the patients cognitively unimpaired at baseline, those with subjective complaints were more likely to develop MCIat follow-up. The regression model confirmed that presence of subjective memory complaints at baseline was an independentpredictor of development of MCI at follow-up. Discussion: This is the first prospective study to explore the relationshipbetween subjective and objective cognitive deficits in newly diagnosed, untreated patients. Our results provide preliminaryevidence that subjective memory complaints might predict future development of MCI.

Keywords

Parkinson disease, cognitive impairment, cognitive testing

Introduction

It is well known that patients with Parkinson disease (PD) mayexhibit prominent nonmotor symptoms including mood andcognitive disturbances, even at the earliest stage.1,2 The Sidneymulticenter study has shown that, over a 15-year follow-upperiod, up to 80% of patients with PD would develop demen-tia,3 which in turn negatively affects their quality of life andsignificantly contributes to institutionalization.4,5 The evidencethat in PD there is a spectrum of cognitive dysfunction, rangingfrom a mild impairment to a frank dementia, has led to borrowthe construct of mild cognitive impairment (MCI) from researchon Alzheimer disease (AD). Mild cognitive impairment is char-acterized by a subjective complaint of cognitive decline reportedby either the patient or the informant, along with cognitive def-icits on formal neuropsychological testing, which results in min-imal or no effect on day-to-day functioning.6 Although MCI hasbeen suggested to predict the development of dementia in PDover the long term,7 it is also clear that there is a wide variabilityamong patients with PD with regard to cognitive functions.8

Longitudinal studies on healthy participants have shownthat subjective memory impairment (SMI) might be a predic-tor of dementia, with 10% of persons with SMI converting to a

diagnosis of MCI over 3 years.9 These data are corroboratedby a growing literature showing that patients with SMI havealterations consistent with incipient AD on structural magneticresonance imaging,10 fluorodeoxyglucose positron emissiontomography (PET),11 amyloid PET,12 and cerebrospinal fluid,13

compared to healthy controls without memory complaints.

1 Sobell Department of Motor Neuroscience and Movement Disorders,Institute of Neurology, University College London (UCL), London, UnitedKingdom2 Department of Psychology, Neuropsychology Laboratory, Second Universityof Naples, Caserta, Italy3 IDC Hermitage—Capodimonte, Naples, Italy4 Center for Neurodegenerative Diseases—CEMAND, University of Salerno,Salerno, Italy5 Department of Neurological Science, University of Naples ‘‘Federico II’’,Naples, Italy6 Department of Motor Sciences, University of Naples ‘‘Parthenope’’, Naples,Italy

Corresponding Author:Paolo Barone, University of Salerno, Center for Neurodegenerative Disease—CEMAND, Via S. Allende, 84081 Baronissi, Salerno, Italy.Email: [email protected]

Journal of Geriatric Psychiatryand Neurology1-6ª The Author(s) 2014Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0891988714532015jgpn.sagepub.com

Subjective memory impairment, defined as a subjective cog-nitive complaint along with normal performance on formalneuropsychological testing, would indeed represent a newconstruct that should fill the gap in between patients with nor-mal cognition and no subjective reports of memory worseningand patients with MCI.

There have been a few studies exploring the relationshipbetween subjective and objective cognitive performances inPD with conflicting results.14-16 Koerts and colleagues foundlittle agreement between subjective complaints and objectivemeasurements of executive functions in PD.14,15 At the opposite,Dujardin et al suggested that objective cognitive decline anddementia might be more frequent among patients with PD hav-ing subjective complaints than in patients without.16 However,in the study by Dujardin et al, more severe cognitive complaintswere not mirrored by more severe objective deficits.16 Severalfactors may contribute to such discrepancies, including samplesize, methodological issues related to the definition of subjec-tive complaints, and the cross-sectional design of these stud-ies. Furthermore, it is has been reported that (1) cognitivefunctions in patients with PD can be affected by presence ofmood disturbances17; (2) patients with PD having subthresholddepression tend to overestimate their cognitive deficits18; and(3) dopaminergic drugs can affect both cognitive performancesand mood.19-21 To address this topic avoiding such potentialbiases, we prospectively screened newly diagnosed, untreatedpatients with PD to evaluate whether subjective memory com-plaints could identify patients with MCI at baseline or predictnew development of MCI during a 2-year follow-up.

Patients and Methods

Patients Enrollment

All the patients included in this study were prospectivelyenrolled in an ongoing research project conducted at themovement disorder center, University Federico II of Naples,Italy. The study was approved by the local ethics committee,and all patients provided written informed consent. Inclusionand exclusion criteria have been extensively described else-where.22-25 In brief, we enrolled newly diagnosed, untreatedpatients with PD (de novo), with symptoms onset less than2 years. Two years after enrollment, all patients underwenta clinical follow-up to confirm the diagnosis of PD accordingto both positive response to dopaminergic therapy and exclusionof atypical symptoms/signs. Detailed clinical information wasobtained from the patient’s history and neurological examina-tion. Parkinsonism was diagnosed by movement disorder spe-cialists experienced in parkinsonian disorders and stagedaccording to Hoehn and Yahr (HY stage).26 The UnifiedParkinson’s Disease Rating Scale part III—motor subscale(UPDRS-III) was used to evaluate motor disability.27

Neuropsychological Evaluation

At baseline, all patients underwent a neuropsychological bat-tery in order to test: (1) memory functions (immediate and

delayed recall of the Rey auditory verbal learning test anddelayed recall of the Rey-Osterrieth complex figure test)28;(2) visuospatial abilities (Benton judgment of line orientationtest, constructional apraxia test—a cognitive task in which apatient has to copy simple and complex figures, thus explor-ing spatial organization and visuoconstructional skills—andclock drawing test)29-31; and (3) attention/executive functions(frontal assessment battery, phonological and semantic fluencytask, copy task of Rey-Osterrieth complex figure test, Corsiblock test, verbal span test, Trail making test: part B minus PartA, and interference task of Stroop color-word test).28,29,32-35 Inthe present study, we did not use Auditory Verbal LearningTest and Rey-Osterrieth complex figure test alternate formsat follow-up since practice effect has been found to be verysmall in patients with early PD.36-38

Such neuropsychological battery was also administered aftera 2-year follow-up. An altered performance in a cognitive testwas defined according to methods recently reported.39 Briefly,for each cognitive test, averaged Z scores were calculated andadjusted according to age, education, and sex on the basis ofa multiple regression analysis performed in a control group.Tests were considered altered when the difference betweenthe actual Z score and the expected Z score was below !1.5.

For the purpose of this study, MCI was diagnosed accord-ing to the Movement Disorder Society (MDS) criteria for MCIin PD (level I)6 but regardless of the presence of subjectivecognitive complaints. In detail, MDS criteria for MCI requirea cognitive decline reported by either the patient or the infor-mant, or observed by the clinician, which does not interferesignificantly with functional independence and is accompa-nied by impairment on at least 2 different neuropsychologicaltests. We have used here only patients’ neuropsychologicalperformances to categorize them as having MCI. Level I MDScriteria for MCI do not allow the identification of specific sub-types of MCI (ie, executive, visuospatial, etc). However, havingour patients been extensively tested for memory functions, wealso subcategorized patients with MCI into 2 groups: (1) patientswith amnesic MCI (ie, with memory deficits) and (2) patientswith nonamnesic MCI (ie, without memory deficits).

Subjective cognitive complaints have been screened accord-ing to the item 12 (ie, ‘‘Problems remembering things that havehappened recently or forgetting to do things’’) of the nonmotorsymptoms questionnaire, a validated and recommended toolfor detection of nonmotor symptoms in PD.40 This has allowedus to categorize patients as having or not memory complaints,regardless of performances on the neuropsychological battery.Depression and anxiety were assessed by mean of the HospitalAnxiety Depression Scale (HADS), HADS depression subscale(HADS-D), and HADS anxiety subscale.41

Statistical Analysis

After Kolmogorov-Smirnov testing for normal distribution,t-test and w2 test, or Fisher exact when expected values weresmall, were performed for group comparisons as appropriate andP < .05 deemed as statistical significant. Finally, multiple

2 Journal of Geriatric Psychiatry and Neurology

logistic regression analyses with forward stepping (likelihoodratio method) were applied to assess whether SMI was anindependent correlate of MCI. In this model, MCI was usedas dependent categorical variable, and SMI, age, age at onset,disease duration, UPDRS-III, and HADS scores were used asindependent variables. Statistical analyses were done withSPSS, version 19.

Results

Sample Characteristics

We enrolled 76 newly diagnosed, untreated patients with PD(47 M and 29 F) with a mean (+standard deviation [SD]) ageof 60.5 + 8.3 years. Mean (+SD) age at onset was 58.6 + 8.2years. Demographic and clinical features of the patients aredetailed in Table 1.

Baseline Neuropsychological Testing

At baseline, 23 of the 76 (30.3%) patients complained aboutmemory issues, while 53 (69.7%) patients did not. Such2 groups did not differ with regard to age, age at onset, diseaseduration, motor disability, and on HADS score (Table 2).

A total of 33 (43.4%) patients fulfilled the criteria for MCI.It was not more prevalent in patients with subjective memorycomplaints than in those without (13/23 vs 20/53, respec-tively, Pearson chi-square [w2] ¼ 2.304, P ¼ .129). Table 2also details baseline prevalence of MCI in patients with andwithout subjective memory complaints. According to bothneuropsychological results and response at item 12 of NMS-Q, we found 13 patients with subjective memory complaintsand MCI (subþMCIþ); 10 patients with subjective memorycomplaints and without MCI (subþMCI!); 20 patients with-out subjective memory complaints but with MCI (sub!MCIþ);33 patients without subjective memory complaints and MCI(sub!MCI!).

Two-Year Follow-Up Neuropsychological Testing

Eleven patients refused the neuropsychological testing (3 subþMCIþ, 2 subþMCI!, 3 sub-MCIþ, and 3 sub-MCI!), thus 65patients were included in the follow-up analyses: 10 subþMCIþ,8 subþMCI!, 17 sub-MCIþ, and 30 sub-MCI!. Among the

38 patients cognitively unimpaired at baseline assessment, 16developed MCI at follow-up: 6 of the 8 patients belonged tosubþMCI group and 10 of the 30 patients belonged to sub-MCI! group. Twenty-two patients did not develop MCI atfollow-up: 2 patients belonged to subþMCI! group and 20patients belonged to sub!MCI! group. Chi-square testshowed a significant association between baseline subjectivememory complaints and presence of MCI at follow-up (w2 ¼4.498, P ¼ .034). We applied regression analyses (with for-ward conditional method) on the 38 cognitively unimpairedpatients at baseline to identify possible predictors of devel-opment of MCI at follow-up. The regression model showedthat presence of SMI at baseline was an independent predic-tor of development of MCI at follow-up, after controlling forconfounder factors such as age, age at onset, disease dura-tion, UPDRS, HY, and HADS scores (B ¼ 1.792, Wald ¼3.931, Exp(B) ¼ 6.000, P ¼ .047). Subtypes of new-onsetMCI were not significantly different between patients withand without subjective complaints (amnesic vs nonamnesic:4 vs 2 in subþMCI! and 6 vs 4 in sub!MCI! group; Fisherw2 ¼ 4.59, P ¼ .10).

Discussion

The present study shows that approximately 25% of de novopatients with PD complain about SMI. Our result is lower thanthe figure by Dujardin et al (32.2%).16 In fact, they alsoassessed the presence of blunted affect, inertia, and loss ofvolition or interest, which explains the higher proportion ofpatients with subjective cognitive complaints.16 Moreover,they did not involve newly diagnosed, untreated patients,which also might explain to some extent such discrepancy.In our study, subjective memory complaints were able topredict future development of MCI over 2 years. The latterresult was confirmed by the regression model, suggestingthat subjective memory complaints might be an independentpredictor of MCI. A few studies assessing the relationshipbetween subjective and objective cognitive decline in PDhave been performed so far, with conflicting results.14-16

Although Dujardin and colleagues found a positive correla-tion between subjective complaints and objective cognitivedecline,16 Koerts failed to confirm such relationship, at leastwith regard to executive functions.14,15 In a way, our resultsare partly consistent with all previous reports. In fact, at base-line, we did not find any association between subjective com-plaints and presence of MCI. Such lack of relationship maysimply be due to the cross-sectional type of analysis. It mayalso reflect the difference in baseline cognitive levels fromwhich individual patients decline (ie, patients with high base-line performance may experience a mild decline subjectively,even if the decline still falls within the normal range). More-over, neuropsychological tests may not always reflect cogni-tive functioning in daily life (ie, low ecological validity), ahypothesis that has also been raised for the lack of agreementbetween subjective and objective executive deficits.14,15 Assuch, our results are in line with Koerts et al.14,15 On the other

Table 1. Baseline Demographic and Clinical Features in Our Patients.

Total Number ¼ 76

Gender, M:F 47:29Age, mean + SD (min-max), years 60.5 + 8.3 (48-71)Age at onset, mean + SD (min-max), years 58.6 + 8.2 (45-70)Disease duration, mean + SD (min-max),

months14.8 + 6.2 (8-22)

UPDRS-III, mean + SD (min-max) 14.6 + 6.9 (6-28)

Abbreviations: F, female; M, male; max, maximum; min, minimum; SD, standarddeviation; UPDRS-III, Unified Parkinson’s Disease Rating Scale, part III—motorsubscale.

Erro et al 3

hand, this is the first prospective study addressing such topic,and we show here that patients with subjective memory com-plaints are more likely to develop MCI over 2 years thanpatients without, confirming previous findings based on thecross-sectional study by Dujardin et al.16

However, it should be noted that, although we have spe-cifically focused on memory complaints, there was not a clearassociation between subjective reports and one specific typeof MCI (ie, amnesic) nor patients with subjective memory com-plaints were more impaired on specific memory tests thanpatients without (data not shown). Subjective ‘‘memory’’ com-plaints predicted future development of both amnesic and non-amnesic types of MCI. This may indicate that patients with PDmay experience different cognitive issues (for instance, diffi-culty keeping track of complex cognitive tasks) and reportthem as memory disturbances. It has been indeed demon-strated that memory deficits in PD are also associated withimpairment of attention allocation, formulation of retrievalstrategies, and effortful learning associated with frontal lobedysfunction.42 It may also be argued that we relied on a singlequestion screening to detect subjective complaints, and thismay be in contrast to the observed cognitive heterogeneityof patients with PD. However, we have deliberately focusedon memory complaints since deficits in posterior functions(ie, memory and visuospatial functions) are supposed to bethe strongest predictors of future development of dementiain PD, reflecting a possible different and additional underly-ing process43,44 than disruption of the frontal–striatal pathway,which instead is considered responsible for the executive dys-function observed in patients with PD. Moreover, very similarapproaches have been already used in non-PD populations.9,10

Obviously, it is likely that the development of more structuredscales, able to discriminate subjective complaints related to eachsubtype/pattern of cognitive impairment, might better identifythose patients with PD who are more prone to develop dementia.

Meta-memory, a construct that may be defined as an indi-vidual’s subjective perception of his or her own memory abil-ity and the tendency to apply strategies to the problem of

increased memory demands, seems to be intact in patientswith PD,45 and this has led to believe that de novo patientswith PD are able to judge their mental changes.46 However,there is also evidence that self-awareness of memory deficitscan be negatively affected by depressive symptoms.47-49 In ourstudy, patients with subjective memory complaints had higherscores on HADS-D than patients without, but this did not reachthe statistical threshold. We have recently reported that sub-threshold depression may also be associated with subjectivememory complaints.18 However, here HADS scores have beenused as covariates in the regression model failing to reach thestatistical threshold, thus excluding any potential bias.

We acknowledge that possible limitations of our study includethe relatively small size of the cohort and the fact that it isnot representative of the whole PD population since we haveenrolled de novo patients per protocol. However, patients withmore advanced PD seem to be more unaware of their ownmemory problems, as suggested by low patient-proxy consis-tency with more severe PD symptomatology.49 While addres-sing on the progression of cognitive decline in PD, it is crucialwhether we can predict such decline. When disease-modifyingtherapies will be available, it will be relevant to early recog-nize patients who are at higher risk of future development ofdementia. In this context, we provide here the preliminaryevidence that subjective memory complaints might predictfuture development of MCI, which in turn is linked to demen-tia. Further research involving larger samples is warranted toconfirm these results.

Authors’ Note

RE contributed in conception, execution, writing the first draft, andreviewing the article for important intellectual concepts; GS, MP,MA, KL, MM, and RA contributed in execution and reviewing the arti-cle for important intellectual concepts; PB contributed in conceptionand reviewing the article for important intellectual concepts; FG con-tributed in execution; and CV contributed in conception, execution, andreviewing the article for important intellectual concepts. Roberto Erroand Gabriella Santangelo contributed equally to the article.

Table 2. Baseline characteristics of the patients, according to the presence of memory complaints.

Patients With MemoryComplaints ¼ 23

Patients Without MemoryComplaints ¼ 53

PValue

Gender, M:F 14:9 32:20 .956Age, mean + SD (min-max), years 60.5 + 7.8 (50-71) 59.8 + 8.3 (48-71) .728Age at onset, mean + SD (min-max), years 58.6 + 7.7 (45-69) 58.5 + 8.4 (47-70) .968Disease duration, mean + SD (min-max), months 15.1 + 7.5 (8-21) 14.7 + 5.7 (8-22) .815UPDRS-III, mean + SD 14.1 + 5.9 14.6 + 7.3 .751HADS, mean + SD 11.8 + 8.1 11.9 + 7.4 .941HADS-D, mean + SD 6.5 + 3.9 5.8 + 4.2 .527HADS-A, mean + SD 5.4 + 4.7 6.1 + 4.1 .469MCI, total, % 56.5 37.7 .129Amnesic-MCI/nonamnesic MCI, % 46.1/53.9 80/20 .032

Abbreviations: M, male; F, female; SD, standard deviation; UPDRS-III, Unified Parkinson’s Disease Rating Scale, part III—motor subscale; HADS, Hospital AnxietyDepression Scale; HADS-D, Hospital Anxiety Depression Scale, Depression subscale; HADS-A, Hospital Anxiety Depression Scale, Anxiety subscale; MCI, mildcognitive impairment.

4 Journal of Geriatric Psychiatry and Neurology

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interestwith respect to the research, authorship, and/or publication of this arti-cle: Dr Marcello Moccia, Marina Picillo, and Roberto Allocca receivehonoraria from the Department of Neurological Sciences, Universityof Naples ‘‘Federico II’’, Italy. Dr Carmine Vitale has received honor-aria for symposia from Boehringer Ingelheim, Lundbeck, Novartis,Schwarz Pharma/UCB, GSK. He has received salary from IDCHermitage-Capodimonte and the University of Naples ‘‘Parthenope,’’Italy. Dr Marianna Amboni and Katia Longo received salary from IDCHermitage-Capodimonte, Italy. Dr Gabriella Santangelo has receivedhonoraria for symposia from Lundbeck. She has received salary fromthe Department of Psychology, Second University of Naples, Caserta,Italy. Dr Maria Teresa Pellecchia has received salary from the Uni-versity of Salerno. Prof Paolo Barone has received honoraria as aConsultant & Advisory Board Memberships for Novartis, SchwarzPharma/UCB, Merck-Serono, Eisai, Solvay, General Electric andLundbeck. He has received salary from the University of Salerno.AQ3

Funding

The author(s) disclosed receipt of the following financial supportfor the research, authorship, and/or publication of this article:Prof Paolo Barone has received research support from BoehringerIngelheim, Novartis, Schwarz Pharma/UCB, Merck-Serono, Solvay,and LundbeckAQ4 .

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