Differences in Subjective Cognitive Complaints Between Non-Demented Older Adults from a Memory Clinic and the Community

Abstract

Background:

Subjective cognitive complaints (SCCs) may represent an early cognitive marker of Alzheimer’s disease (AD). There is a need to identify specific SCCs associated with an increased likelihood of underlying AD.

Objective:

Using the Questionnaire of Cognitive Complaints (QPC), we evaluated the pattern of SCCs in a clinical sample of non-demented older adults in comparison to cognitively healthy community-dwelling volunteers (HV).

Methods:

In total, 142 non-demented older adults from the Czech Brain Aging Study referred to two memory clinics for their SCCs were classified as having subjective cognitive decline (SCD, n = 85) or amnestic mild cognitive impairment (aMCI, n = 57) based on a neuropsychological evaluation. Furthermore, 82 age-, education-, and gender-matched HV were recruited. All subjects completed the QPC assessing the presence of specific SCCs in the last six months.

Results:

Both SCD and aMCI groups reported almost two times more SCCs than HV, but they did not differ from each other in the total QPC score. Impression of memory change and Impression of worse memory in comparison to peers were significantly more prevalent in both SCD and aMCI groups in comparison to HV; however, only the latter one was associated with lower cognitive performance.

Conclusion:

The pattern of QPC-SCCs reported by SCD individuals was more similar to aMCI individuals than to HV. A complaint about memory change seems unspecific to pathological aging whereas a complaint about worse memory in comparison to peers might be one of the promising items from QPC questionnaire potentially reflecting subtle cognitive changes.

Keywords

Mild cognitive impairment prodromal Alzheimer’s disease questionnaire of cognitive complaints subjective cognitive complaints subjective cognitive decline

INTRODUCTION

Subjective cognitive complaints (SCCs) in older adults have been widely studied in patients in prodromal Alzheimer's disease (AD). Concerns regarding a change in cognition obtained from the patient or from an informant became a part of core clinical criteria for mild cognitive impairment (MCI) [1, 2]. In line with the efforts to identify patients with AD as early as possible, even in the preclinical stage of the disease, SCCs in individuals without measurable cognitive deficit have become one of the primary research interests.

In longitudinal studies, SCCs have been found to predict accelerated cognitive decline [3, 4] and increased risk of subsequent dementia [5] (for review, see [6]). Further, in cross-sectional studies, SCCs in cognitively normal older adults have been shown to be associated with the presence of neuroimaging and metabolic biomarker abnormalities consistent with AD pathology [7 –10]. Along with these findings, SCCs in the absence of cognitive impairment have been considered the earliest clinical manifestation of AD, preceding the MCI stage. As a result, the concept of subjective cognitive decline (SCD) was introduced in a recent conceptual framework for research of preclinical AD by the SCD-Initiative Workgroup (SCD-I) [11].

However, community-based studies showed a high prevalence of SCCs in older adults [4 , 12–15] and only a portion of those complaining individuals will develop AD dementia. This may account for some researchers viewing the significance of the SCD concept in preclinical AD as controversial [16]. It may also imply that the current SCD definition is broad and unspecific constituting a heterogeneous population, although it is important to note that most of the studies probably have not specifically reflected the SCD-I criteria yet. Thus, sensitivity and specificity of the true SCD population remains to be further explored.

Different ways how to recruit SCD subjects were shown to bring different associations with AD biomarkers and affective symptomatology. In a recent cross-sectional study by Perrotin and colleagues studying SCD individuals from a memory clinic and community-recruited cognitively normal older adults, amyloid-β deposition was observed in both groups with similarly high level of SCCs; however, SCD individuals from a memory clinic reported more depressive symptoms and had more pronounced hippocampal atrophy [8]. Medical help-seeking behavior may be stimulated by worry associated with SCCs. The so-called cognitive worry was shown to be associated with the greatest risk for conversion to MCI or dementia compared to SCCs without associated worry and no SCCs in cognitively normal older adults at baseline [17, 18].

Classification of SCD is largely based on a subjective report in the context of normal cognitive functioning; however, a standardized assessment of SCCs is still absent [19]. A recent systematic review compared cognitive self-report measures used by 19 international studies [20]. The authors brought preliminary recommendations for instrument selection and expressed a particular need for further research to identify relevant specific items associated with an increased likelihood of early AD.

The Questionnaire of Cognitive Complaints (QPC; from French Le Questionnaire de Plainte Cognitive) was originally developed to help physicians in primary care identify individuals with cognitive impairment due to AD [21, 22]. It is a brief and easy to administer tool which is listed on the French Greco database as one of the screening questionnaires and widely used in clinical praxis in France. It comprises three types of questions that have been recently proposed to differentiate between normal and pathological aging [20, 23]: 1) decline in memory compared to the previous level; 2) memory functioning compared to individuals of the same age group; and 3) other specific cognitive complaints beyond memory. Prevalence and distribution of QPC-SCCs in a sample of cognitively healthy community-dwelling volunteers aged 60 or older was shown in our recent study [15]. The total QPC score reflected more closely depressive symptomatology than cognitive performance. Lower memory performance was specifically linked to Impression of worse memory in comparison to peers and Spatial orientation difficulties. The most prevalent complaints (Word finding difficulties, Difficulties with recalling past events, and Impression of memory change) were not related either to depressive symptomatology or cognition in that sample. As we discussed, these findings support the notion that some complaints are specific for pathological aging, while others seem to be part of normal aging. It also supports recommendations of the SCD-I Workgroup [20] who stimulated researchers to focus rather on individual items than the total score which usually does not allow to weight endorsement of individual complaints. However, findings from a community-dwelling sample are not easily transferred into the clinical setting, unless confirmed in the clinical setting. Studies on the medical-help seeking SCD population are lacking.

Building on our previous research [15] and following the recommendations of the SCD-I, we aimed to analyze the pattern of SCCs using the Czech version of the QPC in a sample of 1) individuals seeking help at a memory clinic for their cognitive complaints without cognitive deficit based on a comprehensive neuropsychological assessment (SCD), 2) individuals seeking help at a memory clinic for their cognitive complaints, who fulfilled criteria for amnestic MCI (aMCI), and to compare it to 3) cognitively healthy community-dwelling volunteers without SCCs for which they would seek for medical help (HV). Second, we aimed to examine the total QPC score and specific QPC-SCCs in relation to depressive symptomatology and cognitive performance.

We hypothesized a continuum in the frequency of QPC-SCCs ranging from HV to SCD and aMCI individuals and searched for QPC-SCCs specific for each of those groups: we expected Memory change and Impression of worse memory in comparison to peers to be particularly linked to cognitive performance.

METHODS

Participants

The clinical study sample (SCD and aMCI) consisted of 142 subjects aged 60 and older participating in the Czech Brain Aging Study (CBAS) and was recruited at two centers: 1) Memory Clinic, Department of Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital; 2) Memory Center by International Clinical Research Center, St. Anne’s University Hospital Brno. Patients were referred to these memory clinics by general practitioners, neurologists, psychiatrists, and geriatricians for SCCs reported by the patients and/or by their informants. The nature and intensity of complaints were verified by a semi-structured interview with an experienced clinician. All patients underwent clinical and laboratory evaluations, brain MRI, and comprehensive neuropsychological examination. A cognitive neurologist together with a clinical neuropsychologist classified the patients as aMCI or SCD based on results of neuropsychological examination during the standard diagnostic meeting.

aMCI patients (n = 57) met published clinical criteria for aMCI, including memory complaints reported by a patient or a caregiver, evidence of memory dysfunction on neuropsychological testing, generally intact activities of daily living, and absence of dementia [1]. Memory impairment was established when the patients scored ≥1.5 SD on at least one memory test below the mean of age- and education-adjusted norms [24]. Both single domain (memory impairment only) and multiple domain (memory impairment plus impairment of at least one other cognitive domain) MCI patients were included in the aMCI group. To diminish the risk of self-perception bias caused by anosognosia only individuals with Mini-Mental State Exam (MMSE) ≥24 were included [25].

SCD patients (n = 85) met published criteria for SCD [11] including a self-experienced persistent decline in cognitive capacity within the last 5 years in comparison with a previously normal status and unrelated to an acute event and normal age-, gender-, and education-adjusted performance on standardized cognitive tests. Cognitively unimpaired individuals were not included into the SCD group if their main motivation for the consultation at the memory clinic was positive family history of dementia, but not subjective cognitive complaints.

Individuals with a history of neurological disease potentially leading to cognitive impairment and disturbances in mobility (history of stroke, traumatic brain injury, neuroinfection, Parkinson’s disease, etc.), psychiatric diseases including major depressive disorder, or abnormal neurological examination were not included. Furthermore, individuals with significant vascular changes on MRI (Fazekas scale >2), or with major depressive symptomatology on 15-item Geriatric Depression Scale (GDS-15 > 10) were not included in either of the medical-help seeking groups (aMCI, n = 15; SCD, n = 22).

HV group comprised 82 community-dwelling volunteers without SCCs for which they would ever seek or intended to seek for medical help which was ascertained in a structured interview by an experienced clinician. They were age, education, and gender matched to SCD individuals and were chosen from the participants of a normative study of healthy aging (NANOK) [26]. General exclusion criteria for NANOK were history of neurological disease potentially causing brain impairment and disturbances in mobility (history of stroke, traumatic brain injury, neuroinfection, Parkinson’s disease, etc.), an acute phase of serious mental disorder (e.g., major depressive disorder), current radiotherapeutic or chemotherapeutic treatment, alcohol or substance abuse, and impaired sensory perception not possible to be corrected by sensory aids. Additionally, only those participants were included in whom the absence of cognitive impairment was ascertained. Probable cognitive impairment was established when the subjects scored ≥1.5 SD below the mean of age- and education-adjusted norms on at least one of the following tests: MMSE, Rey Auditory Verbal Learning Test sum of trials 1–5 (RAVLT 1–5), RAVLT delayed recall after 30 minutes, and Trail Making Test A and B. The cut-off score of 1.5 SD was set so that it resembles that used for the aMCI group. All HV participants completed a comprehensive neuropsychological battery in a single assessment.

All participants in this study signed written informed consent that was approved by a local ethics committee (Motol University Hospital, St. Anne's University Hospital Brno, and National Institute of Mental Health). The procedures were in accordance with the Helsinki Declaration of 1975 and later revision in 2000.

Measures

Evaluation of SCCs: QPC

All participants were administered the Czech version of the QPC, which was based on an original French 10-item yes/no questionnaire assessing the presence of cognitive difficulties in the last six months [22, 27]. The Czech version was made based on a translation from French to Czech by an experienced translator, followed by a back-translation from Czech to French by a translator blinded to the original French version. The discrepancies were consulted and based on the consensus between the two translations the final version was developed to preserve the original meaning as accurately as possible. The QPC was translated into English in cooperation with a native English speaker and the final English version was approved by the author of the questionnaire, already for the purpose of our previous study [15]. The first two items of the QPC inquire about general memory abilities, while the remaining eight items inquire about more particular cognitive complaints with a focus on memory. The items also cover difficulties with spatial orientation, language, instrumental activities, or personality change. The exact wording of all items is presented in Fig. 1. For each item, we indicate a key name for ease in reporting findings.

Fig.1

QPC, Questionnaire of cognitive complaints. Exact phrasing and key names. Questions are related to last six months.

Neuropsychological measures

All participants underwent a comprehensive neuropsychological battery that included measures of global cognitive function (MMSE [28]), attention (Trail Making Test A (TMT A) [29]; Prague Stroop Test – Dots, (PST-D) [30]), memory (RAVLT [31]), executive function (Trail Making Test B (TMT B) [29]; Prague Stroop Test–Color (PST-C) [30]), and language (phonemic verbal fluency – letters N, K, P; semantic verbal fluency–animals [32]). All participants were also administered a self-report GDS-15 [33] to evaluate the severity of depressive symptomatology. We adjusted the GDS-15 by subtracting the cognitive item from the total score [item number 10: “Do you feel you have more problems with memory than most?”; (adjusted GDS-15)], so that the analyses exploring the association between SCCs, depressive symptomatology and cognition are not biased by a shared variance between the QPC and GDS-15 measures.

Statistical analyses

To evaluate between-groups differences in age and years of education, we performed a parametric one-way analysis of variance (ANOVA), with Tukey post hoc test, as the assumption of normality was not violated (values of skewness and curtosis ranged from –1 to +1). The Pearson Chi-Square test evaluated differences in gender proportions. To evaluate between-groups differences in background neuropsychological characteristics and severity of depressive symptomatology, we performed a non-parametric Kruskal-Wallis H test followed by pairwise Mann-Whitney U tests with a Bonferroni correction for multiple comparisons, as the assumption of normality was violated (values of skewness and curtosis ranged outside –1 to +1). To evaluate between-groups differences in the total QPC score, we performed a parametric one-way ANOVA, with Tukey post hoc test, as the assumption of normality was not violated (values of skewness and curtosis ranged from –1 to +1). Between-groups differences in frequency of reported specific QPC-SCCs were compared using the Pearson Chi-Square test, to control for multiple comparisons the Bonferroni correction was applied. To evaluate the relation between SCCs, depressive symptomatology and cognition the non-parametric Spearman rank-order correlation was performed, followed by the non-parametric partial rank correlation. Demographic characteristics (age, education, and gender) were not associated with the total QPC score or the specific QPC-SCCs, so only adjusted GDS-15 was used as a covariate. Additional Multiple Linear Regression was conducted to determine whether both depressive symptomatology (adjusted GDS-15) and the diagnostic group predicted the total QPC score (outcome variable).

The significance level (alpha) was set at (p≤0.05) throughout the analyses; the adjusted level of significance according to Bonferroni correction for multiple comparisons is reported for each analysis in the Results section. To report effect sizes, partial eta² was calculated for ANOVA and Kruskal-Wallis H test, Cohen’s d for Tukey post hoc test, effect size r score for Mann-Whitney U test, and Cramer’s V for Pearson Chi-Square test. Cognitive scores were transformed into z-scores. Cognitive composite z-score of memory, attention, executive function, and language were calculated as the averages of z-score of administered neuropsychological tests for each cognitive domain. The scores for TMT A, TMT B, and PST were reversed before being transformed into z-scores.

All statistical analyses were run using IBM SPSS Statistics 20 for Windows.

RESULTS

Demographic and neuropsychological characteristics of groups

Demographic and neuropsychological characteristics of groups are summarized in Table 1. There were no group differences in years of education (F(2, 220) = 1.94, p = 0.14, partial eta² = 0.08). As expected, there was a main effect of group on age (F(2, 221) = 9.92, p < 0.001, partial eta² = 0.08). Tukey post hoc tests indicated that SCD and HV were younger than aMCI (both ps < 0.001) but they were not significantly different from each other (p = 0.98). There were no group differences in gender proportions (χ²(2) = 4.876, p = 0.087). Further, a Kruskal-Wallis H test showed that there was a statistically significant between-group difference in adjusted GDS-15 score (χ²(2) = 15.04, p = 0.001; partial eta² = 0.07). Post hoc pairwise Mann-Whitney U tests showed that aMCI and SCD reported more depressive symptoms on adjusted GDS-15 than HV (U = 1204.5, p = 0.002, and U = 1828.5, p = 0.001, respectively), with significant differences even after Bonferroni correction for multiple comparisons (both ps < 0.016), but aMCI and SCD were not significantly different from each other (U = 1402.0, p = 0.86). As for neuropsychological background, aMCI performed significantly worse than SCD and HV in all neuropsychological measures (ps≤0.016), SCD and HV did not differ from each other, except for RAVLT 1–5 in which HV surprisingly performed worse (U = 2599.0, p = 0.012).

Table 1

Demographic and neuropsychological characteristics of groups

	aMCI (n = 57)			SCD (n = 85)		HV (n = 82)
	Mean (SD)	d^a	d^b	Mean (SD)	d^a	Mean (SD)
Age	73.6 (5.9)^{***, †††}	0.71	0.69	69.2 (6.7)	0.02	69.4 (5.9)
Education	13.7 (3.2)	0.22	0.33	14.7 (2.7)	0.11	14.4 (2.9)
Female, n (%)	29 (50.9)			58 (68.2)		54 (65.9)
QPC	3.7 (2.2)^***	0.98	0.16	4.0 (2.3) ^***	1.13	1.8 (1.6)
	Mean (SD)	r^a	r^b	Mean (SD)	r^a	Mean (SD)
GDS-15	3.1 (2.1)^‡	0.14	0.00	3.2 (2.4)^‡	0.14	1.6 (1.7)
Adjusted GDS-15	2.5 (1.9)^‡	0.08	0.00	2.6 (2.3)^‡	0.08	1.4 (1.6)
MMSE	27.1 (1.5)^‡, ‡‡	0.25	0.33	28.9 (1.1)	0.01	28.6 (1.2)
RAVLT 1–5	32.4 (9.2)^‡, ‡‡	0.47	0.56	51.9 (7.8)^‡	0.04	48.7 (8.2)
RAVLT 30	3.3 (3.3)^‡, ‡‡	0.54	0.56	10.6 (2.8)	0.01	10.1 (2.4)
TMT A	54.2 (22.5)^‡, ‡‡	0.13	0.10	40.6 (12.6)	0.00	38.7 (9.5)
TMT B	177.1 (109.3)^‡, ‡‡	0.37	0.28	91.5 (30.5)	0.03	81.2 (25.9)
PST-D	16.2 (3.5)^‡, ‡‡	0.10	0.27	13.8 (2.9)	0.02	14.1 (2.4)
PST-C	42.8 (18.0)^‡, ‡‡	0.23	0.19	30.3 (9.7)	0.00	28.9 (8.4)
S-VF	17.9 (6.3)^‡, ‡‡	0.16	0.20	23.6 (5.9)	0.00	22.7 (5.5)
P-VF	35.3 (12.3)^‡, ‡‡	0.20	0.18	46.3 (11.2)	0.00	47.5 (12.9)

^*p≤0.05, ^**p≤0.01, ^***p≤0.001; in comparison to HV; ^†††p≤0.001, in comparison to SCD (one-way Analysis of Variance with Tukey post hoc test); ^‡p < 0.016, statistically significant difference after Bonferroni correction for multiple comparison in comparison to HV; ^‡‡p < 0.016, statistically significant difference after Bonferroni correction for multiple comparison in comparison to SCD (Mann–Whitney U test); d^a: Cohen’s d effect size in comparison to HV; d^b: Cohen’s d effect size in comparison to SCD; r^a: Effect size r score in comparison to HV; r^b: Effect size r score in comparison to SCD; GDS-15, Geriatric Depression Scale, 15-item version; adjusted GDS-15, the cognitive item subtracted; MMSE, Mini-Mental State Examination; RAVLT, Rey Auditory Verbal Learning Test, sum of trials 1–5; RAVLT, Rey Auditory Verbal Learning Test, delayed recall after 30 minutes; TMT, Trail Making Test; PST-D, Prague Stroop Test – dots; PST-C, Prague Stroop Test – color; S-VF, semantic verbal fluency (animals); P-VF, phonemic verbal fluency (letters N, K, P).

Pattern of SCCs according to groups

There was a significant main effect of group on the total QPC score (F(2, 221) = 27.82, p < 0.001, partial eta² = 0.20). Both clinical groups, aMCI and SCD, reported two times more QPC-SCCs relative to HV (both ps≤0.003), but they did not differ from each other (p = 0.441); see Table 1.

Specific QPC-SCCs endorsement according to groups is presented in Fig. 2. Both clinical groups (aMCI and SCD) reported with significantly higher frequency than HV seven out of ten specific QPC-SCCs (Impression of memory change, Impression of worse memory in comparison to peers, Difficulties with recalling past event, Spatial orientation difficulties, Forgetting about past experiences, Limitation in daily activities, and Personality change), but they did not differ from each other, except for Difficulties with recalling past events, which was the only QPC-SCC reported with significantly higher frequency by aMCI than by SCD. There were two QPC-SCCs (Word finding difficulties, and Forgetting about appointments) reported with significantly higher frequency by SCD in comparison to both aMCI and HV but with similar level of frequency by aMCI and HV. Losing things was reported with higher frequency by SCD and aMCI in comparison to HV, however, the difference between aMCI and HV did not reach statistical significance. The between-groups differences should be treated cautiously in the complaints with low prevalence (Forgetting about appointments, Losing things, Spatial orientation difficulties and Forgetting about past experiences).

Fig.2

Between-group differences in frequency of self-reported specific QPC-SCCs using the Pearson Chi-Square Test; ^**p≤0.016, ***p≤0.001, statistically significant difference after Bonferroni correction for multiple comparison (alpha level adjusted for comparison of 3 groups: 0.05/3 = 0.016).

Total QPC score in relation to depressive symptomatology and cognition

The total QPC score was not associated with any of the demographic characteristics (age, education, and gender; all ps≥0.106), so that these variables were not used as covariates in further analyses. Higher total QPC score was moderately associated with higher depressive symptomatology (adjusted GDS-15; ρ= 0.43, p < 0.001); this association remained significant after Bonferroni correction for multiple comparisons (alpha level adjusted for comparison of 9 variables, p≤0.005). According to the additional Multiple Linear Regression, the combination of the adjusted GDS-15 score and the diagnostic group significantly predicted the total QPC score, F(2,188) = 21.13, p < 0.001. 18% of the total QPC score was explained by the model. However, only the adjusted GDS-15 score significantly contributed to the model (adjusted GDS-15: β= 0.43, p < 0.001; diagnostic group: β= 0.01, p = 0.88). Exploring the Collinearity Statistics, the variables did not account for an overlapping variance.

The total QPC score was not associated with MMSE or cognitive domains, which remained the same even after adjusting for depressive symptomatology (all ps≥0.067). Table 2 displays the associations between the total QPC score, demographic characteristics, depressive symptomatology, global cognitive functioning, and cognitive domains.

Table 2

The association between the total QPC score and demographic variables, depressive symptomatology, and cognition

	rho¹	B Correction	rho²
Age	0.10	ns	–
Education	0.0023	ns	–
Gender	0.086	ns	–
adjusted GDS-15	0.43^***	sig.	–
MMSE	–0.12	ns	–0.12
Memory^†	–0.045	ns	–0.022
Attention^†	–0.11	ns	–0.069
Executive function^†	–0.11	ns	–0.13
Language^†	–0.10	ns	–0.098

^*p < 0.05, ^**p < 0.01, ^***p < 0.001; ¹non-parametric Spearman rank-order correlation; ²non-parametric partial rank correlation, controlled for adjusted GDS-15; ^†values expressed in composite scores, calculated as the averages of z-score of administered neuropsychological tests for each cognitive domain; adjusted GDS-15, Geriatric Depression Scale, 15-item version, the cognitive item subtracted; MMSE, Mini-Mental State Examination; B Correction, Bonferroni Correction for multiple comparisons (alpha level adjusted for comparison of 9 variables: 0.05/9 = 0.005); numbers are rounded to two significant figures.

Specific QPC-SCCs and their relation to depressive symptomatology and cognition

Globally, all the specific QPC-SCCs were weakly to moderately associated with higher depressive symptomatology, the associations remained significant after Bonferroni correction for multiple comparisons (all ps≤0.007), except for Forgetting about appointments (p = 0.047) and Limitation in daily activities (p = 0.032).

The associations between specific QPC-SCCs and depressive symptomatology and cognitive performance are displayed in Table 3a and 3b. Five out of ten QPC-SCCs were weakly associated with at least one cognitive domain or global cognition measure (Impression of worse memory in comparison to peers, Difficulties with recalling past events, Forgetting about past experiences, Limitation in daily activities, and Personality change), three of them remained significant even after the stringent Bonferroni correction for multiple comparison (Impression of worse memory in comparison to peers, Difficulties with recalling past events, and Limitation in daily activities).

Table 3a

The associations between specific QPC-SCCs, depressive symptomatology, and cognition, without controlling for depressive symptomatology

	Adjusted GDS-15	MMSE	Memory^†	Attention^†	Executive^†	Language^†
Specific QPC-SCCs	rho (p)
1 Impression of memory change	0.29 (<0.001)^*	–0.088 (0.19)	0.036 (0.60)	–0.021 (0.76)	–0.013 (0.84)	0.004 (0.95)
2 Impression of worse memory in comparison to peers	0.25 (<0.001)^*	–0.12 (0.060)	–0.11 (0.10)	–0.13 (0.054)	–0.19 (0.0045) ^*	–0.15 (0.020)
3 Difficulties with recalling past events	0.28 (<0.001)^*	–0.15 (0.021)	–0.18 (0.0058) ^*	–0.16 (0.014)	–0.19 (0.0031) ^*	–0.14 (0.030)
4 Forgetting about appointments	0.14 (0.047)	0.023 (0.73)	0.20 (0.0026)^*	0.14 (0.029)	0.15 (0.027)	0.087 (0.19)
5 Losing things	0.19 (0.0065)^*	–0.097 (0.16)	0.024 (0.72)	0.017 (0.80)	0.024 (0.72)	–0.038 (0.57)
6 Spatial orientation difficulties	0.19 (0.0066)^*	–0.063 (0.35)	–0.048 (0.47)	–0.012 (0.85)	–0.53 (0.43)	–0.069 (0.30)
7 Forgetting about past experiences	0.20 (0.0053)*	–0.055 (0.42)	–0.095 (0.16)	–0.087 (0.19)	–0.17 (0.010)	–0.031 (0.64)
8 Word finding difficulties	0.20 (0.0054)^*	0.25 (<0.001)^*	0.22 (<0.001)^*	–0.020 (0.76)	–0.20 (0.0028)*	0.14 (0.033)
9 Limitation in daily activities	0.15 (0.032)	–0.24 (<0.001) ^*	–0.20 (0.0027) ^*	–0.16 (0.016)	–0.25 (<0.001) ^*	–0.15 (0.017)
10 Personality change	0.43 (<0.001)^*	–0.15 (0.026)	–0.052 (0.44)	–0.13 (0.041)	–0.12 (0.067)	–0.16 (0.013)

Non-parametric Spearman rank-order correlation; ^†values expressed in composite scores, calculated as the averages of z-score of administered neuropsychological tests for each cognitive domain; ^* p≤0.008, statistically significant correlation coefficient after Bonferroni correction for multiple comparisons [alpha level adjusted for comparison of 6 variables (adjusted GDS-15, MMSE and cognitive domains), 0.05/6 = 0.008]; adjusted GDS-15, Geriatric Depression Scale, 15-item version, the cognitive item subtracted; MMSE, Mini-Mental State Examination; numbers are rounded to two significant figures.

Table 3b

The associations between specific QPC-SCCs and cognition, controlling for depressive symptomatology

	MMSE	Memory^†	Attention^†	Executive^†	Language^†
Specific QPC-SCCs	rho (p)
1 Impression of memory change	–0.087 (0.23)	0.070 (0.33)	0.030 (0.68)	0.0073 (0.92)	0.026 (0.72)
2 Impression of worse memory in comparison to peers	–0.12 (0.081)	–0.088 (0.23)	–0.093 (0.20)	–0.18 (0.013)	–0.14 (0.047)
3 Difficulties with recalling past events	–0.15 (0.031)	–0.16 (0.026)	–0.12 (0.088)	–0.18 (0.011)	–0.13 (0.072)
4 Forgetting about appointments	0.026 (0.72)	0.22 (0.0023)^*	0.17 (0.017)	0.16 (0.027)	0.099 (0.17)
5 Losing things	–0.095 (0.19)	0.046 (0.53)	0.051 (0.48)	0.038 (0.60)	–0.025 (0.73)
6 Spatial orientation difficulties	–0.061 (0.40)	–0.028 (0.70)	0.021 (0.77)	–0.040 (0.58)	–0.056 (0.44)
7 Forgetting about past experiences	–0.052 (0.47)	–0.076 (0.30)	–0.055 (0.45)	–0.16 (0.025)	–0.017 (0.81)
8 Word finding difficulties	0.26 (<0.001)^*	0.25 (<0.001)*	0.013 (0.85)	0.21 (0.0025)*	0.16 (0.027)
9 Limitation in daily activities	–0.24 (<0.001)^*	–0.18 (0.010)	–0.14 (0.056)	–0.24 (<0.001)*	–0.15 (0.039)
10 Personality change	–0.15 (0.030)	–0.0076 (0.91)	–0.074 (0.31)	–0.10 (0.15)	–0.15 (0.039)

Non-parametric partial rank correlation, controlling for adjusted GDS-15; ^†values expressed in composite scores, calculated as the averages of z-score of administered neuropsychological tests for each cognitive domain; ^*p≤0.008, statistically significant correlation after Bonferroni correction for multiple comparisons [alpha level adjusted for comparison of 6 variables (adjusted GDS-15, MMSE and cognitive domains), 0.05/6 = 0.008]; MMSE, Mini-Mental State Examination; numbers are rounded to two significant figures.

After adjusting for depressive symptomatology, all the five QPC-SCCs remained associated with worse cognitive performance (Limitation in daily activities, Difficulties with recalling past events, Impression of worse memory in comparison to peers, Forgetting about past experiences, and Personality change), however, only recognition of Limitation in daily activities was significantly associated with worse executive performance (ρ= –0.24, p < 0.001, and worse MMSE score, ρ= –0.24, p < 0.001), after applying the stringent Bonferroni correction for multiple comparisons.

DISCUSSION

The QPC is a relatively brief and easy to administer tool for SCCs assessment which is listed in the French Greco database as one of the screening questionnaires recommended to be used in clinical praxis for SCCs assessment. Despite the recommendation studies on the population of SCD individuals have been lacking. Using the QPC, SCD and aMCI individuals did not differ from each other in the number of SCCs or depressive symptoms, but both medical-help seeking groups reported two times more SCCs and three times more depressive symptoms in comparison to demographically matched and cognitively similar healthy community-dwelling volunteers. In terms of the total QPC-score, current results do not support the hypothesized continuum ranging from healthy volunteers to SCD and aMCI individuals in our sample. Instead, SCD individuals seem to be closer to aMCI individuals, which is congruent with findings of a previous study [34].

The total QPC score was significantly related to higher depressive symptomatology but not to cognitive performance, the diagnostic group itself was not predictive of the QPC score. This result is in agreement with previous findings [8, 35] and can be explained by the same level of higher depressive symptomatology and cognitive complaints in both clinical groups compared to HV, but differences in cognitive performance in standard neuropsychological battery between aMCI and SCD group where aMCI individuals scored by definition lower than SCD.

The causality of relationship between SCCs and depressive symptomatology in non-demented older adults has not been clarified yet. Some authors argue that particularly in SCD individuals depressive symptomatology is the primary cause of SCCs [16]. Second, depressive symptoms may be triggered by awareness of cognitive decline in comparison to previous level not captured using traditional neuropsychological tests originally designed for identification of cognitive deficit at the MCI stage; or third, depressive symptoms may also be an independent early manifestation of underlying AD neuropathological process in both aMCI and SCD individuals [23, 36]. The last-mentioned hypothesis was supported by findings of two recent longitudinal studies with a 14- and 28-year follow-up [38, 39]. The largest risk of dementia was associated with depressive symptoms occurring approximately 5 years before dementia onset, while depression occurring earlier throughout the lifespan did not significantly increase the risk of dementia. In a recent cross-sectional study [8], subclinical depression together with hippocampal atrophy was indeed more prevalent in medical-help seeking SCD individuals compared to community-recruited older adults with similarly high levels of SCCs. The authors suggested that cognitively normal older adults with a higher level of depressive symptomatology in whom SCCs are associated with medical-help seeking behavior may be further along the AD trajectory in comparison to subjects who do not evaluate their SCCs to be distressing enough to seek for medical help. Taken together, the stronger association between the total QPC score and depressive symptomatology in adjusted GDS-15 questionnaire in comparison to cognitive performance in our sample cannot be explained as only depression causing the SCCs and further studies are needed to clarify the causality of relationship.

The pattern of specific QPC-SCCs reported by SCD individuals was also much closer to the pattern of QPC-SCCs endorsed by aMCI individuals than by healthy volunteers. Impression of memory change and Impression of worse memory in comparison to peers are complaints earlier proposed as potentially useful for identifying individuals at preclinical and prodromal stage of AD [23]. In our sample, they were reported with the almost highest prevalence by both medical-help seeking groups in comparison to relatively low prevalence in healthy community-dwelling volunteers.

There was an association between Impression of worse memory in comparison to peers and worse cognitive performance. The association remained significant after accounting for depressive symptomatology, but it did not survive the Bonferroni correction. With respect to its comparably high prevalence in both medical-help seeking groups, we consider the association with cognitive performance as an important finding. Thus, these findings support the presumed potential of the complaint to reflect subtle cognitive changes.

Impression of memory change was not associated with cognitive performance and was reported almost by one third of healthy volunteers consistently with our previous paper [15]. In a previous cohort-based study by Amariglio, a complaint about Change in memory was acknowledged by more than 50% of non-demented subjects [14]. In line with that and with our previous study showing such a high prevalence in cognitively healthy older adults, it seems that a complaint about memory change as worded in the QPC questionnaire does not specifically reflect pathological aging. However, in a cross-sectional study acknowledgement of progressive memory change was shown to differentiate cognitively healthy older adults with high amyloid-β load, who are supposed to be in the preclinical stage of AD, from those with low amyloid-β load [40]. Further, in a longitudinal study acknowledgement of worsening memory which was associated with worry was shown to be a greater risk factor for conversion to dementia compared to worsening memory without worry in cognitively healthy participants [17]. Thus, based on our results and previous reports it is possible that simple complaint about memory change is rather nonspecific, unless associated with progressive nature or worry.

We identified one specific QPC-SCC, Difficulties with recalling past events, showing the hypothesized continuum in prevalence (HV < SCD < aMCI). There was another one, Limitation in daily activities, showing the same trend, although the difference between aMCI and SCD did not reach the statistical significance. The frequency with which these two QPC-SCCs were reported by groups was reflected in the association with worse MMSE, memory and executive performance, which remained significant for Limitation in daily activities even after adjusting for depressive symptomatology. It suggests that endorsement of these two complaints may reflect more severe cognitive decline. This assumption is supported by results of a previous study using QPC, showing a higher prevalence of complaint about Limitation in daily activities in patients with early and mild AD in comparison to cognitively healthy controls [22].

Despite our expectations, Forgetting about appointments and Word finding difficulties were reported with significantly higher prevalence by SCD individuals compared to both aMCI and healthy controls. Word finding difficulties were acknowledged by three quarters of SCD individuals which is reflected by association with better cognitive performance. The similar prevalence in aMCI and community-dwelling cognitively healthy older adults supports the notion that subjective word finding difficulty constitutes rather a part of normal aging and does not necessarily relate to anomia due to AD neuropathology which is present rather later on the AD trajectory [41].

The three remaining complaints, Losing things, Spatial orientation difficulties, and Forgetting about past experiences, were reported by a smaller portion of participants relative to other QPC-SCCs and were not associated with cognition. Though, they were also reported with a significantly higher prevalence by both medical help-seeking groups than by healthy controls. We suppose that difficulties with Losing things and Forgetting about past experiences do not appear in prodromal stages of AD. In the current study, only aMCI individuals with MMSE≥24 were included to diminish the risk of self-perception bias caused by anosognosia occurring in late prodromal and dementia stage of the disease [25]. On the other hand, findings about prevalence of spatial orientation complaints are not consistent. The relatively low prevalence reported by all groups is in contrast to findings of another recent study [42], where 55% of aMCI, 68% of SCD, and even 33% of healthy controls complained about their spatial navigation. However, spatial navigation difficulties were evaluated on a four-point Likert scale and it is likely that individuals may tend to endorse more difficulties when evaluating on a scale in comparison to yes/no decision. Still, spatial orientation impairment has been already well-established as an AD cognitive marker occurring very early in the course of the disease [43]. Thus, a complaint about spatial orientation difficulty should be treated with concern.

In a recent commentary by Buckley and colleagues, the question of how to utilize the SCD concept in terms of its predictive information about the risk of cognitive decline was discussed [44]. To analyze individual complaints and seriously consider the recruitment setting is the recent direction in SCD research. Medical help-seeking SCD individuals were shown to have a more pronounced marker of neurodegeneration [8] and to be more likely to progress to MCI than SCD individuals from the general population [18], thus, they were proposed to be further along the AD trajectory [8, 19]. Building on these assumptions, the current study examining the pattern of QPC-SCCs in a clinical sample of aMCI and SCD subjects expands on our previous one [15] which studied the prevalence of individual QPC-SCCs and their relation to depressive symptomatology and cognition in a sample of community-dwelling cognitively healthy volunteers. Still, there are several limitations that need to be considered in the interpretation of the current results.

The absence of AD biomarker evidence in our current cross-sectional study does not allow us to determine in what portion of our individuals SCD is really AD-related despite the increasing evidence that SCCs are more likely to be related to AD pathology when acknowledged by worried medical help-seeking cognitively healthy individuals. In our medical-help seeking SCD group, 30% of the SCD individuals did not report memory change and 47% of the SCD individuals did not report worse memory in comparison to peers. This could suggests that these individuals do not fit the traditional definition of SCD [11]. One explanation could be a discrepancy between information provided by the individuals in a structured questionnaire and during the clinical interview. Another possible explanation of this discrepancy could be that SCD individuals who did not report memory change and worse memory in comparison to peers experienced decline in other than memory domain. The main inclusion criterion to classify a subject as SCD was the intensity of recently developed cognitive complaints (not limited only to memory domain) that motivated the consultation at a memory clinic which was verified by a semi-structured interview with an experienced clinical. Further research is needed to investigate positive and negative predictive value of specific QPC-SCCs in a clinical sample of SCD individuals in a longitudinal setting, ideally in individuals with AD biomarker evidence. The self-perception bias caused by anosognosia is commonly associated with the dementia stage; however, it may be present even at the MCI stage [45, 46]. Although we tried to diminish the risk, still, it is possible that in some aMCI individuals the self-report was slightly affected by their reduced self-awareness. As for the selection of the HV group, it should be noted that the cognitive criterion was overly strict and the HV group is not fully representative of the cognitively healthy older population. However, the cut-off score of –1.5 SD was set with the aim to select cognitively healthy volunteers from the community who were psychometrically comparable to the SCD group as much as possible.

Conclusion

In conclusion, the pattern of cognitive complaints reported by medical help-seeking SCD individuals is similar to that of aMCI individuals. Both medical help-seeking groups endorsed not only a higher number of SCCs, but also a higher number of depressive symptoms in comparison to demographically matched and cognitively similar community-dwelling healthy volunteers, despite not meeting criteria for clinical diagnosis of depressive disorder. Our findings support the notion that analysis of the pattern of reported QPC-SCCs seems to be more informative than the total score when evaluating the risk of non-normative cognitive decline. A complaint about memory change seem to be unspecific to pathological aging whereas a complaint about worse memory in comparison to peers might be one of the promising items from QPC questionnaire potentially reflecting subtle cognitive changes.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the Charles University project GA UK No. 135215, 692818 and 176317, by the project no. LQ1605 from the National Program of Sustainability II (MEYS CR), Ministry of Health, Czech Republic–conceptual development of research organization, University Hospital Motol, Prague, Czech Republic Grant No. 00064203, Institutional Support of Excellence 2. LF UK Grant No. 699012, by the Ministry of Health of the Czech Republic, project AZV 16-27611A, by the Czech Science Foundation under grant number 18-06199S, and by the AVASTipendium for human brain in cooperation with the Alzheimer Foundation.

Authors’ disclosures available online ().

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