Can Subjective Memory Complaints Identify Aβ Positive and Aβ Negative Amnestic Mild Cognitive Impairment Patients?

Abstract

Background:

The use of biomarkers, in particular amyloid-β (Aβ) changes, has allowed the possibility to identify patients with subjective memory complaints (SMCs) and amnestic mild cognitive impairment (aMCI) who suffer from Alzheimer’s disease (AD). Since it is unfeasible that all patients with aMCI could presently undergo biomarkers assessment, it would be important that SMCs might contribute to identify the aMCI patients who have AD amyloid pathology.

Objectives:

To know whether aMCI patients with amyloid biomarkers (Aβ⁺) present greater SMCs as compared to those without amyloid biomarkers (Aβ^-).

Methods:

Participants were selected from a cohort of nondemented patients with cognitive complaints and a comprehensive neuropsychological evaluation, on the basis of 1) diagnosis of aMCI; 2) detailed assessment of memory difficulties with the SMC Scale; and 3) known amyloid status. The amyloid status was determined on the basis of either CSF Aβ_1–42 concentration or amyloid PET imaging.

Results:

Of the 176 patients with aMCI studied, 90 were Aβ⁺ and 86 were Aβ^-. The two groups did not differ in terms of age, gender, and education. The SMC total score was not significantly different in the Aβ⁺ aMCI patients (9.48±4.18) when compared to the Aβ^- aMCI patients (10.52±4.57). The Aβ⁺ aMCI patients had lower scores on the MMSE and memory/learning tests, but not on the Geriatric Depression Scale, when comparing to the Aβ^- aMCI patients.

Conclusions:

Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD.

Keywords

Alzheimer’s disease amnestic amyloid-β anosognosia depressive symptoms mild cognitive impairment subjective memory complaints

INTRODUCTION

Memory complaints are considered the initial and the most prominent symptom of Alzheimer’s disease (AD), leading patients to seek clinical assistance. Recent revised criteria that incorporate biomarkers maintain the report of memory decline by patients or informants as part of the core diagnostic features for AD [1, 2]. Subjective memory complaints (SMCs) thus represent an important symptom in clinical practice. Previous studies showed that individuals with SMCs are at greater risk to develop dementia [3, 4]. A systematic review of longitudinal studies with cognitively normal individuals at baseline proposed that SMCs may predict future cognitive decline [5]. In a meta-analysis, older people with SMCs but without objective memory deficits are twice as likely to develop dementia as individuals without SMCs [6]. On the other hand, memory complaints are very common in the general population [7 –9] and in the community, in addition to the elderly, many young individuals consider they are forgetful [10]. Additionally, the clinical significance of SMCs may depend upon the settings where the participants are recruited, for instance, elderly individuals who seek medical help in a memory clinic or hospital outpatient setting reported more prominent memory difficulties as compared to the individuals in the community [11]. The clinical significance of SMCs may also depend upon the way they are assessed, either by a single question regarding actual memory performance or by using formal self-report questionnaires. The Subjective Memory Complaints (SMC) scale [3] is such a questionnaire, comprising items considered representative of common memory complaints, that was found useful to discriminate specific types of SMCs in a clinical setting [12].

The concept of amnestic mild cognitive impairment (aMCI) characterizes a transitional state between normal cognitive aging and dementia. Patients with aMCI have memory complaints and objective impairment in memory and/or other cognitive domains, without major repercussions in daily life, and are not demented. aMCI is a condition that often progresses to dementia, mainly AD [13, 14]. However, aMCI can have other etiologies [15]. In recent years, the clinical use of biomarkers has allowed the possibility of diagnosing AD in patients that present with aMCI. These biomarkers reflect pathological alterations in the brain characteristic of AD, in particular amyloid-β (Aβ) biomarkers that ascertain whether an individual is in the AD continuum [16]. The presence of amyloid pathology may be determined by measuring low Aβ_1–42 concentrations in cerebrospinal fluid (CSF), and/or finding abnormal brain deposits of Aβ with amyloid brain positron emission tomography (PET) scan [17]. In spite of the extraordinary advance that the development of biomarkers represent, both in investigational and clinical settings, biomarkers are still quite expensive and in some cases invasive, and it is recognized that is unfeasible that all patients with aMCI could presently undergo testing of the whole set of biomarkers [18]. Therefore, it would be important to understand whether a clinical interview assessing SMCs and neuropsychological deficits could predict the aMCI patients who have amyloid pathology (Aβ⁺) and have AD. Comparison of aMCI patients regarding their amyloid status has shown that patients who are Aβ⁺ have more prominent episodic memory deficits, as well as deficits in other cognitive domains, as would be expected from the presence of AD [19, 20]. In the present study, we advance the hypothesis that aMCI patients with biomarkers of amyloid pathology have more SMCs than those without amyloid pathology. More specifically, we test whether the Aβ⁺ aMCI patients present a higher SMC scale total score compared to the Aβ^- aMCI patients.

MATERIAL AND METHODS

Participants

Participants were selected from the Cognitive Complaints Cohort (CCC), established in a prospective study conducted at Faculdade de Medicina da Universidade de Lisboa, to investigate the cognitive stability or evolution to dementia in patients with cognitive complaints, based on a comprehensive neuropsychological assessment and other biomarkers. The CCC recruited nondemented patients with cognitive complaints who did a comprehensive neuropsychological evaluation during the period from 2007 to 2018, at the participating institutions, namely, Memoclínica, a private memory clinic in Lisbon; and the Dementia Clinic, Serviço de Neurologia do Centro Hospitalar e Universitário de Coimbra. At these institutions, patients also underwent clinical history, neurological examination, laboratorial evaluation, and brain imaging (CT or MRI). More detailed information regarding the CCC establishment was previously published [21]. The present study was conducted according to the declaration of Helsinki and was approved by the local ethics committee. The participants’ informed consent was obtained before any procedure.

Inclusion criteria

Diagnosis of MCI, adapted from Petersen et al. [13], corresponding to aMCI:

Memory complaints present at the clinical interview;

Abnormal memory function, documented by a cut-off of the Logical Memory test delayed recall score [22, 23] and/or the California Verbal Learning Test long delay free recall score [24] 1.0 SD below the norms for age and education. This cut-off value was adopted considering that the use of a lower cut-off value could exclude subjects that from a clinical point of view suffered from aMCI [24]. Previous studies observed that the use of the 1.0 SD cut-off in MCI patients had predictive value for the development of dementia [25].

Normal general cognitive function, determined by the Mini-Mental State Examination (MMSE) [26] within normal values for the Portuguese population [23].

No or a minimal impairment in activities of daily living, provided by the Instrumental Activities of Daily Living Scale (IADL) [27] with no more than one item from the IADL scale being altered [28].

Assessment with the SMC scale [3].

Known amyloid status, either by quantification of CSF Aβ_1–42 or amyloid PET imaging (see below).

Exclusion criteria

Presence of neurological (stroke, brain tumor, significant head trauma, epilepsy) or psychiatric disorders that may induce cognitive deficits; patients with major depression according to the DSM-IV-TR [29] or serious depressive symptoms, indicated by a score > 10 in the Geriatric Depression Scale short-version (GDS₁₅) [30 –32].

Presence of systemic illness with cerebral impact (hypertension, metabolic, endocrine, toxic and infectious diseases).

History of alcohol abuse or recurrent substance abuse or dependence.

Medication use having possible interference with cognition.

Seriously reduced vision or other sensory deficits likely to hinder assessment.

Presence of dementia according to the DSM-IV-TR [29].

The diagnosis of aMCI was established by an experienced neurologist, after multidisciplinary consensus using all available clinical information.

Neuropsychological assessment

A comprehensive neuropsychological assessment was performed by the same group of trained neuropsychologists in each institution and comprised the following instruments:

MMSE [26, 23]. Normal values for the Portuguese population are > 27 for more than 11 years of education and > 22 for 11 or less years of education.

Battery of Lisbon for the Assessment of Dementia [22, 23]. This is a comprehensive neuropsychological battery, including tests from the Wechsler Memory Scale [33], evaluating multiple cognitive domains like memory and learning, attention and executive functions, abstract reasoning and visuoconstructional abilities, orientation and arithmetic and has been validated for the Portuguese population. In the present study we used Logical Memory immediate and delayed free recall for the assessment of learning and memory abilities.

GDS [30 –32]. The GDS is a questionnaire that evaluates the existence and the degree of depressive symptomatology. For the present study, we used the short-form (15 items) of the self-report instrument, adapted for the Portuguese population [32].

IADL [27]. The IADL is a tool that evaluates daily self-care activities. The Portuguese version was used [28].

California Verbal Learning Test (CVLT) [34, 24]. The CVLT evaluates immediate recall, learning (trials A1-A5), short delay free and cued recall, long delay free and cued recall and recognition. For the present study we used the A1-A5 score and the long delay free recall score. Values were available only for a subset of participants (n = 78).

SMC Scale [3, 35]. This scale comprises 10 individual items concerning difficulties in daily life memory tasks (see the table on the SMC scale results), with total scores ranging from 0 (absence of complaints) to 21 (maximal complaints score) and are considered representative of common memory complaints [3]. The SMC scale was always applied prior to any other neuropsychological assessment.

Amyloid status

The presence of amyloid pathology was determined by detecting low Aβ_1–42 concentrations in the CSF, and/or finding abnormal brain deposits of Aβ with amyloid PET scan. A high agreement between Aβ_1–42 concentrations in the CSF and amyloid PET scan findings was documented previously, supporting the strong connection of these two measures in aMCI and AD [36].

Lumbar puncture and CSF handling followed established protocols [37]. The levels of Aβ_1–42, total tau (t-tau), and phosphorylated tau (p-tau) were measured using commercially available enzyme-linked immunosorbent assays (INNOTEST® β-amyloid (1–42), Innotest hTau Ag, and Innotest Phospho-tau (181P); Innogenetics, Ghent, Belgium). Quantification of CSF biomarkers was done at each center and considering the recognized site assay variability [38], positivity was determined using locally available cut-off values. For the purpose of the present study, only the CSF levels of Aβ_1–42 were considered.

Amyloid PET scans used the Pittsburgh Compound B (¹¹C-PIB) and were performed in the same scanner (Philips PET/CT Gemini GXL), preceded by a low-dose brain CT acquisition for attenuation correction (Institute of Nuclear Science Applied to Health, ICNAS, University of Coimbra). PiB-PET images were classified as amyloid positive or negative based on a support vector machines (SVM) local classifier, which uses the voxelwise brain grey matter standardized uptake value ratio (SUVR) and the cerebellar grey matter as reference region [39].

The participants completed the SMC scale and performed the neuropsychological assessment before being informed about their amyloid status.

Statistical analysis

Statistical analysis was performed using the IBM SPSS Statistics 24 for Windows (IBM Corp., Armonk, NY) package. Significance was set at p < 0.05.

Demographic data were compared between groups with the Student’s t tests for numerical variables and χ² Pearson tests for categorical data.

The z scores for logical memory (immediate and delayed free recall) and CVLT (A1-A5 and long delay free recall) were calculated according to the age and education norms for the Portuguese population with the equation [z = (x-mean)/SD] and were compared between Aβ⁺ aMCI and Aβ^- aMCI patients with the Student’s t test. Comparisons of MMSE scores, GDS scores, and total scores of the SMC scale between Aβ⁺ aMCI and Aβ^- aMCI patients were also done with the Student’s t test. A subsequent exploratory analysis comparing the individual SMC items between the two groups was performed with Student’s t test without statistical correction for multiple comparisons. Correlation analyses between the demographical and neuropsychological variables and the SMC total score were performed with the Pearson’s correlation test.

Sample size was a priori estimated from a power analysis using the Power and Precision software (v.4; BioStat; Englewood, NJ). Assuming the value for the total SMC score in patients with aMCI reported in a similar clinical setting (10.3±4.2) [11] recruitment of 160 aMCI participants (80 amyloid positive and 80 amyloid negative) would allow detection of a 20% difference in the total SMC scores between the two groups, assuming common variance, power = 81%, α= 0.05 and a 2-tailed test.

RESULTS

Amyloid status

One hundred and seventy-six patients were recruited. The amyloid status was determined using CSF Aβ_1–42 concentration and/or PiB-PET, and participants classified as either being Aβ-positive (Aβ⁺) (n = 90) or Aβ-negative (Aβ-) (n = 86). In the Aβ⁺ patients, the amyloid status was determined based on CSF Aβ_1–42 in 45, PiB-PET imaging in 23 and both methods in 22 patients. In the Aβ^- patients, the amyloid status was determined based on CSF Aβ_1–42 in 65, PiB-PET imaging in 7 and both methods in 14 patients.

Demographic and neuropsychological data

No significant statistical differences were found between Aβ⁺ aMCI and Aβ^- aMCI patients regarding age, gender, education, and the GDS total score (Table 1). The Aβ⁺ aMCI patients had lower scores on the MMSE, Logical Memory immediate and delayed free recall, and CVLT A1-A5 and long delay free recall when comparing with the Aβ^- aMCI patients (Table 1). The SMC total score was not significantly different in Aβ⁺ aMCI patients when compared to Aβ^- aMCI patients (Table 2). No differences were found on the SMC total score either when age and the GDS total score were modelled as covariates (results not shown). Furthermore, when performing an exploratory analysis, without correction for multiple comparisons, no significant statistical differences were observed in the 10 individual SMC items between the Aβ⁺ aMCI and Aβ^- aMCI patients (Table 2).

Table 1

Demographic and clinical characteristics

	aMCI_totaln = 176	aMCI Aβ⁺n = 90	aMCI Aβ^-n = 86	p
Age at first assessment, y, mean (SD)	66.7 (9.7)	67.9 (8.2)	65.4 (11.0)	0.096^a
Duration between symptoms onset and	3.6 (3.1)	3.6 (3.2)	3.7 (3.0)	0.923^a
first assessment, y, mean (SD)
Gender, male/female, n (% female)	74/102 (58)	36/54 (60)	38/48 (56)	0.341^b
Education, y, mean (SD)	8.7 (4.8)	9.3 (4.9)	8.2 (4.6)	0.135^a
MMSE, mean (SD)	27.0 (2.6)	26.2 (2.6)	27.9 (2.2)	<0.001 ^a, *
Logical Memory
Immediate free recall, z-score, mean (SD)	–1.4 (1.1)	–1.7 (1.1)	–1.1(1.1)	0.001 ^a, *
Long delay free recall, z-score, mean (SD)	–1.7 (1.2)	–1.9 (1.1)	1.5(1.3)	0.040 ^a, *
California Verbal Learning Test^c
A1-A5, z-score, mean (SD)	–3.1(1.4)	–3.4 (1.4)	–2.7 (1.4)	0.027 ^a, *
Long delay free recall, z-score, mean (SD)	–3.0 (1.8)	–3.7 (1.9)	–2.4 (1.6)	0.009 ^a, *
Geriatric Depression Scale, mean (SD)	4.6 (3.0)	4.2 (2.9)	4.8 (3.1)	0.401^a

MMSE, Mini-Mental State Examination; A1-A5, learning trials A1-A5; SD, standard deviation; ^aStudent’s t-test; ^bχ² Pearson test; ^cThe CVLT was performed in a subset of patients (aMCI Aβ⁺, n = 41; aMCI Aβ^-, n = 34). *Statistically significant (p < 0.05).

Table 2

Subjective memory complaints in aMCI patients

	aMCI_total	aMCI Aβ⁺	aMCI Aβ^-	p*
SMC1, mean (SD)	2.00 (0.77)	1.98 (0.83)	2.02 (0.71)	0.695
Do you have any complaints concerning your memory?
SMC2	1.02 (0.67)	0.99 (0.66)	1.06 (0.67)	0.493
Do other people find you forgetful?
SMC3	0.94 (0.98)	0.88 (0.93)	1.00 (1.03)	0.411
Do you ever forget names of family members or friends?
SMC4	1.71 (0.88)	1.66 (0.88)	1.77 (0.89)	0.402
Do you often forget where things are left?
SMC5	1.12 (0.79)	1.04 (0.78)	1.20 (0.79)	0.198
Do you often use notes to avoid forgetting things?
SMC6	0.57 (0.49)	0.52 (0.50)	0.63 (0.49)	0.158
Do you ever have difficulties in finding particular words?
SMC7	0.07 (0.25)	0.06 (0.23)	0.08 (0.27)	0.499
Did you ever lose your way in neighborhood?
SMC8	0.82 (0.61)	0.82 (0.55)	0.81 (0.66)	0.928
Do you think more slowly than you used to?
SMC9	0.84 (0.66)	0.78 (0.67)	0.91 (0.64)	0.193
Do your thoughts ever become confused?
SMC10	0.83 (0.65)	0.78 (0.65)	0.88 (0.66)	0.284
Do you have concentration problems?
SMC scale, total score, mean (SD)	9.94 (4.3)	9.48 (4.18)	10.52 (4.57)	0.171

SMC, subjective memory complaint; SD, standard deviation. Scoring of items 1, 3, and 4:0: no; 1: yes, but no problem; 2: yes, problem; 3: yes, serious problem. Scoring of items 2 and 5:0: no; 1: yes, sometimes; 2: yes, often. Scoring of items 6 and 7:0: no; 1: yes. Scoring of items 8, 9 and 10:0: no; 1: yes; 2: yes, serious problem. *Student’s t test.

Correlations between SMCs and demographic and neuropsychological data

As showed in Table 3, a statistically significant negative correlation was observed between the SMC total score and age in both Aβ⁺ aMCI (r = –0.296; p = 0.005) and Aβ^- aMCI patients (r = –0.387; p < 0.001). A statistically significant positive correlation was observed between the SMC total score and the Logical Memory delayed free recall in Aβ⁺ aMCI patients (r = 0.252; p = 0.023) but not in Aβ^- aMCI patients. A statistically significant positive correlation was observed between the SMC total score and the GDS total score in both Aβ⁺ aMCI (r = 0.489; p = 0.001) and Aβ^- aMCI patients (r = 0.594; p < 0.001). No correlations were found between the SMC total score and education, MMSE total score and LM immediate free recall in both Aβ⁺ aMCI and Aβ^- aMCI patients.

Table 3

Correlations between SMC total score and demographic and neuropsychological variables

		SMC scale total score
		r ^†	p
Age	aMCI Aβ⁺	–0.296	0.005*
	aMCI Aβ^-	–0.387	<0.001*
Education	aMCI Aβ⁺	0.198	0.061
	aMCI Aβ^-	0.182	0.098
MMSE	aMCI Aβ⁺	0.144	0.199
	aMCI Aβ^-	0.157	0.162
Logical Memory
Immediate free recall	aMCI Aβ⁺	0.038	0.738
	aMCI Aβ^-	–0.008	0.944
Delayed free recall	aMCI Aβ⁺	0.252	0.023*
	aMCI Aβ^-	0.123	0.292
Geriatric Depression Scale	aMCI Aβ⁺	0.489	0.001*
	aMCI Aβ^-	0.594	<0.001*

SMC, subjective memory complaint; MMSE, Mini-Mental State Examination; ^†Pearson correlation coefficients; *Statistically significant (p < 0.05).

DISCUSSION

The present study aimed to test whether aMCI patients with amyloid pathology (Aβ⁺) have more SMCs, assessed through the SMC scale, than aMCI patients without amyloid pathology (Aβ^-). As expected from the recruitment criteria, aMCI patients as a whole reported prominent SMCs. Also, as expected, Aβ⁺ aMCI patients performed worse on episodic memory (logical memory immediate and delayed free recall) when comparing to the Aβ^- aMCI patients, a result in agreement with previous studies [19 , 20]. However, in contrast to the initial hypothesis, the Aβ⁺ aMCI patients did not translate these more severe memory deficits into greater SMCs. Furthermore, an exploratory analysis on the 10 individual items of the SMC scale did not provide any hint that a specific type of complaint might be particularly emphasized by Aβ⁺ aMCI patients.

Interestingly, several studies performed in clinically asymptomatic older individuals found that those with Aβ⁺ status, that is, in the preclinical phase of AD, reported greater SMCs than those who are Aβ^- [41 –43] (but see [44]).

The present study was performed in the clinical phase, i.e., patients with aMCI who have both SMCs and objective memory decline. At this stage, it seems that Aβ⁺ aMCI individuals may mitigate the report of SMCs in spite of obvious objective memory deficits. A previous study showed that aMCI patients who would convert to dementia, and thus would probably have AD pathology, actually presented lower scores on several items of the SMC scale at the baseline, compared to the aMCI patients who would remain stable [12]. Accordingly, SMCs were less in patients at late stages of aMCI as compared with early stages, when the complaints were appraised by the patient, but not by the caregiver [45]. One possible explanation is that Aβ⁺ aMCI patients are anosognosic regarding their actual objective memory performance. Anosognosia was originally described as disrupted awareness of motor perceptual deficits [46]. Anosognosia, in the sense of lack of awareness for memory deficits, is recognized as a common symptom in patients with dementia due to AD, assuming clinical relevance regarding the reliability of memory complaints [47, 48]. The ability to recognize memory deficits is already impaired at the aMCI stage of the disease [49 –51]. Measuring discrepancy scores between objective memory performance and SMCs, Vannini and collaborators indeed found that Aβ⁺ aMCI patients were anosognosic towards their memory functions [42]. Interestingly, in the correlation analysis we found that Aβ⁺ aMCI patients with a better score in the logical memory delayed free recall were able to report more SMCs, suggesting that anosognosia may indeed develop during progression of the disease.

The association of SMCs with depressive symptoms has been documented previously, in healthy elderly [52, 53], as well as in patients with aMCI [54]. Accordingly, in the present work a positive correlation between the SMC scale total score and the GDS total score was found, both in Aβ⁺ and in Aβ^- aMCI patients, but no difference in the GDS total score was observed between the two groups. From this point of view, the presence of SMCs and memory deficits in the Aβ^- aMCI patients could not be directly attributed to depressive etiology. It must be noted that, in the present study, individuals with higher levels of depressive symptomatology (GDS₁₅ > 10) were excluded. The question of the etiology of aMCI cases that do not show AD pathology still remains, and is the subject of intensive present research. Stroke and relevant cerebrovascular disease in brain imaging were excluded in the present study, but Aβ^- aMCI patients might be at an initial stage of other neurodegenerative disorder, like frontotemporal dementia or the Lewy body dementia-Parkinson’s disease continuum [19]. A limitation of the present work is that a thorough neuroimaging study, detailing regional brain atrophy and white matter changes, was not performed.

An interesting finding of the present study was an inverse correlation between age and the SMC scale total score, both in Aβ⁺ and in Aβ^- aMCI patients. A large study showed that SMCs are frequent in healthy individuals across the life span, but younger participants more frequently reported that they were told by others to be forgetful [8]. People generally believe that some degree of memory impairment is expected as they get older, and older people may display more tolerance regarding minor memory difficulties [55].

Different instruments have been used to appraise SMCs [56]. We chose the SMC scale to assess memory complaints, an instrument composed of 10-items that includes inquiry about everyday memory and questions like thinking more slowly, confusion of thoughts and concentration problems, considered to be representative of common memory complaints and useful to predict future conversion to dementia [3]. It is acknowledged that the use of different instruments can lead to variability in detecting associations between SMCs and clinical findings [57]. More detailed approaches, as thematic analysis through a semi-structured interview, were proposed to apprehend the phenomenological experience of memory complaints in a more comprehensive way, and might be useful to capture the whole complexity of the subjective impression about memory at this stage of the disease process.

In conclusion, evaluating SMCs does not seem helpful to identify, among the patients with aMCI, those who have AD.

Footnotes

ACKNOWLEDGMENTS

The authors thank Memoclínica for the facilities provided. This work was supported by a grant from Fundação para a Ciência e Tecnologia (FCT) - PTDC/MED-NEU/27946/2017.

Authors’ disclosures available online ().

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