Impact of Recruitment Methods in Subjective Cognitive Decline

Abstract

Background: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer’s disease dementia, but little is known about its influence in subjective cognitive decline (SCD).

Objective: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.

Methods: We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.

Results: The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.

Conclusion: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

Keywords

Alzheimer’s disease patient recruitment research subject recruitment sampling studies subjective cognitive decline

INTRODUCTION

With the growing interest in the preclinical study of neurodegenerative diseases, subjective cognitive decline (SCD) has been suggested as a risk marker of Alzheimer’s disease (AD) [1]. Several studies have found an increased risk of future mild cognitive impairment (MCI) and dementia in SCD [2 –5]. However, this relationship has not been confirmed in other cross-sectional and longitudinal studies [6 –8]. A possible explanation would be different definitions of SCD among studies and methodological reasons, such as sampling and recruitment methods that can lead to selection bias[9, 10].

Various studies have investigated the influence of setting and enrollment methods on sample characteristics. For example, MCI participants recruited by population-based sampling had better memory performance and less APOE ɛ4 carriers compared to patients referred by clinicians [11]. Similarly, MCI clinical samples have shown a higher annual rate of conversion to dementia than community samples, and this source of recruitment has been associated with increased risk of incident dementia [12].

Studies that have explored this question in AD dementia patients have demonstrated that participants recruited from population based settings are younger, more self-reliant, and with better global cognitive scores than patients referred from general practice [13, 14]. Also, community-based cohorts tend to have less severe AD pathology and more frequency of vascular and mixed pathology compared to clinical based samples [15].

One meta-analysis that has investigated the risk of dementia and MCI among elderly SCD subjects, has compared the rate of conversion from SCD to MCI and dementia in community dwelling participants and a specialists setting, demonstrating no difference in the progression risk between samples [4]. Another study about the factors that determine help-seeking behavior in SCD subjects from a memory clinic vs population-based sample, found that subjects from the clinical cohort had lower scores on memory self-efficacy and quality of life, with more memory concerns than their community counterparts, due to a positive family history of dementia [16].

Nevertheless, there is insufficient information about the impact of enrollment methods in sample characteristics of subjects with SCD. Therefore, the aim of this study was to compare the clinical features, neuropsychological performance and frequency of APOE ɛ4 allele carriers in subjects with SCD drawn from two different settings.

MATERIAL AND METHODS

Sample selection

Memory Unit (MU) sample

In 1996, Fundació ACE developed a multidisciplinary approach to treat patients with neurodegenerative diseases with the establishment of a Memory Unit (MU) [17]. At the MU, all patients undergo standardized neurobehavioral examinations, neuropsychological [18, 19] and social workevaluations [17], as well as appropriate laboratory and neuroimaging studies. These patients constitute a clinical cohort, given that they are referred by their primary care physician or medical specialists. Clinical samples are a type of convenience sample, where individuals are select based on ease of recruitment. Other types of convenience samples are the community-based volunteer samples and mixed samples (a combination of the two foregoing types) [20].

Open House Initiative (OHI) sample

Since 2008, our center has been performing an Open House Initiative (OHI) where free cognitive screening is offered to Barcelona citizens older than 49 years old through social media, the Fundació ACE website, radio, etc. At the OHI visit, there is collected data regarding medical history, education level, medication and family history. Until 2013, the screening diagnosis was based on Mini-Mental State Examination (MMSE) [21, 22] and 7-minute test [23, 24]. Since then, we have been using the MMSE and the Face Name Associative Memory Exam (FNAME) [25, 26]. Additionally, examination for mood disorders with the Hospital Anxiety and Depression Scale (HAD) [27] and a quantitative scale for subjective cognitive complaints with a Spanish modified version of the Memory Failures in Everyday questionnaire (MFE-30) [28] was incorporated. To date, over 1,800 subjects have been evaluated in the OHI, of which approximately 50% have SCD. Since the OHI assessment is a screening, all tested individuals are invited to receive a complete evaluation at the MU of Fundació ACE to confirm the diagnosis. Given these characteristics, this cohort could be considered as an intermediate point between a medical help-seeking and a community-based volunteer sample [20].

Using these two methods of recruitment, and their corresponding samples (MU and OHI), we compared the features of subjects with SCD. Both samples are from the same main population of Barcelona, Spain.

Eligibility criteria

For the purpose of this research, we selected individuals evaluated at Fundació ACE from January 2013 to August 2015. SCD diagnosis was done using the proposed research criteria for pre-MCI SCD by Jessen et al. [1]. The following two criteria must be present: 1) Self-experienced persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event AND 2) Normal age-, gender-, and education-adjustedperformance on standardized cognitive tests. The following two criteria must be absent: 1) Mild cognitive impairment, prodromal AD, or dementia, and 2) Cognitive symptoms can be explained by a psychiatric or neurologic disease (apart from AD), medical disorder, medication, or substance abuse. Moreover, we assessed subjective cognition in a qualitative manner by asking two consecutive questions: 1) “Do you feel like your memory is worsening?” and 2) “Do you worry about your memory problems?” The required answers are dichotomic (Yes/No). A positive answer to the first question was used to diagnose SCD, and a positive answer in the second question to evaluate the presence of worry. We decided to use this qualitative assessment because none of the existent quantitative questionnaires have been fully validated and data are lacking regarding their comparative accuracy to predict preclinical AD. By contrast, these two questions are easy to implement and have shown to predict subsequent decline in longitudinal follow-up [3].

All subjects had normal cognitive performance in Fundació ACE neuropsychological battery (NBACE) [18, 19]. None had sensory impairment that could interfere with cognitive evaluation or medical, psychiatric or neurological conditions related to SCD; and there was less than 4 months between neurological and neuropsychological examinations.

This study was approved by the ethics committee of the Hospital Clinic i Provincial (Barcelona, Spain) and all participants signed a written informed consent prior to any evaluation, in accordance with Spanish biomedical laws (Law 14/2007, July 3rd, about biomedical research; Royal Decree 1716/2011, November 18th).

Neuropsychology

All individuals underwent a cognitive screening with MMSE [21, 22] and the memory subtest of 7-Minute screening [23, 24]^. All the participants were administered NBACE, a comprehensive battery described elsewhere [18, 19] that includes tests sensitive to orientation, memory, language, and executive, visuoconstructive, visuospatial, and visuoperceptive functions. Test included in NBACE are: verbal learning, delayed recall, and recognition memory from the Third Version of Weschler Memory Scale (WMS-III), digit span forward and backwards, phonetic and semantic verbal fluency, 15 item Boston Naming Test, block design and similarities tests of the Third Version of Weschler Adult Intelligence Scale (WAIS-III), Poppelreuter’s Test, 15 Objects Test, automaticinhibition of the Syndrom Kurtz Test (SKT), Luria’s Clock Test, imitation praxis, and global orientation (temporal, spatial and personal).

APOE genotyping

Genomic DNA was extracted using 200μl of human whole blood by Maxwell^® 16 Blood DNA purification kit (Promega) according to the manufacturer’s instructions. APOE rs7412 and rs42358 markers were genotyped by high resolution melting (HRM) technique, using the Eco Real-Time PCR system (Illumina). Primers design was previously described by Calero et al. [29].

Statistical analysis

The statistical analysis were performed using IBM SPSS 20 (SPSS Inc., Chicago, IL). All data were examined for normality, skew, and restriction of range. The results are presented as mean±SD for normally distributed continuous variables, median [range] for non-normally distributed continuous variables, and number and percentage for categorical variables. Chi-Squared test, parametric Student t-test, and Mann-Whitney U test were used to compare the demographic characteristics, neuropsychological performance, and APOE ɛ4 carriers. Bonferroni adjustment was used for multiple testing comparisons and those variables <0.003 were considered statistical significant for the logistic regression analysis (LRA). Then, a LRA with conditional entrance was used to examine the association between the cognitive performance and the type of recruitment method, adjusting for gender and years of education.

RESULTS

A total of 486 subjects with SCD were evaluated at Fundació ACE from January 2013 to August 2015 : 255 from the OHI of which 86.3% met the inclusion criteria, and 231 from the MU where the percentage of included individuals was 45.9%. Thus, 326 subjects were analyzed: 220 from the OHI (67%) and 106 from the MU (33%). Table 1 summarizes the demographic features, MMSE scores, family history of dementia, and personal history of depression among groups.

The OHI sample was made up mostly of women (167 [75.9%] versus 68 [64.2%], p = 0.028), had more years of education (12.15 [3.71] versus 10.70 [3.80], p = 0.001), a higher percentage of family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001), and better performance in MMSE (29.60 [0.72] versus 29.09 [1.02], p < 0.001) (yet the score in both groups can be considered normal and this variable showed a moderate effect size). However, subjects who proceeded from the OHI did not differ from those of the MU either in age (63.42 [7.84] versus 64.52 [9.84], p = 0.317) or personal history of depression (OHI 38 [17.7%] versus MU 24 [23.8%], p = 0.204).

After asking both groups if they were worried about their memory problems, the OHI and MU samples demonstrated similar preoccupation (positive answer 196 out of 220 [89.1%] versus 100 out of 106 [94.3%], p = 0.125).

With regard to neuropsychological examination, the OHI sample performed better than the MU sample in: attention, verbal memory (verbal learning, recognition memory and working memory), language (visual confrontation naming), ideomotor praxis, executive functions (automatic inhibition, phonetic verbal fluency and abstract reasoning), and visuospatial function; without statistically significant differences between groups in: constructional praxis, verbal long-term memory, and visuoperception (Table 2). After Bonferroni correction, automatic inhibition capacity, verbal learning, recognition memory, visuospatial function, phonetic verbal fluency, semantic verbal fluency, and abstract reasoning were considered statistical significant. These variables were analyzed in a LRA adjusted by gender and years of education, finding that the domains: automatic inhibition (Wald = 16.76, p < 0.005, OR = 1.11; CI 95% 1.06–1.17), recognition memory (Wald = 5.02, p < 0.05, OR = 0.78; CI 95% 0.63–0.97) and abstract reasoning (Wald = 9.64, p < 0.005, OR = 0.77; CI 95% 0.65–0.91) kept their statistically significant difference, although these last two variables showed a moderate and large effect size, respectively.

We analyzed APOE genotypes in 267 subjects (59 subjects with missing data). Both groups presented similar frequency of heterozygotes for APOE ɛ4 allele (OHI 48 [24.0%] versus MU 17 [25.4%], p = 0.821). The percentage of APOE ɛ4 homozygotes was 3.07% in the whole sample (10 subjects). The small number of ɛ4/ɛ4 homozygotes prevented the comparison among study groups.

DISCUSSION

We have found differences between SCD subjects conventionally ascertained in a memory clinic from those evaluated at the OHI. We consider that observed differences could be attributable specifically to type of recruitment method.

To our knowledge, this is the first study that analyzes the impact of two recruitment methods in sample characteristics of SCD subjects. Most of the studies focusing on this issue have compared sampling procedures in cognitively normal adults. Thus, in order to compare our results with the studies published previously, we have used the studies of cognitively normal subjects or controls, because they probably include individuals with SCD; although we acknowledge that cognitively normal constitutes a different group that share a normal neuropsychological performance with SCD subjects.

Subjects from the OHI were more likely women, had higher educational level, and more frequency of family history of dementia than those from the MU. These results are consistent with other studies that have found differences in these demographic features between cognitively normal individuals from a convenience sample and a population-based cohort [11 , 31]. In contrast to other studies that have found that population-based cohorts tend to be older than convenience samples, we did not note differences in age [11 , 31]. Yet, these studies do not differentiate the type of convenience sample (community-based volunteers from medical help-seeking sample). Additionally, the discrepancy identified between our results and other studies in age, may be due to the fact that the OHI sample is a midpoint between volunteers and a medical help seeking sample, given that we offer free cognitive screening to the population and the possibility of enrollment in a scientific study is proposed after this evaluation, so the participation in research is not a prerequisite to be examined [20]. Maybe this last characteristic makes the OHI sample a type of recruitment method more similar to a community-based volunteer’s cohort than a medical help-seeking sample, because although these subjects are looking for cognitive assessment, they have not been referred from a primary care physician or a specialist, and they volunteer for the examination but not directly for a memory study.

Personal history of depression did not differ among the recruitment methods studied, and a similar result has been obtained by Ramakers et al. who did not found differences in levels of depressive and anxiety symptoms when comparing a clinical versus a community-based cohort [16].

Memory concern has been proposed as a feature of SCD plus since it is a characteristic that could increase the likelihood of preclinical AD in subjects with SCD [1], because self-reported concerns regarding memory impairment have been found related to future cognitive decline and conversion to AD dementia [32 –35]. In the present study, both samples showed similar concern about their cognitive performance. We have not found a comparison of this variable according to the recruitment method in studies published previously, so it would be interesting to investigate in future prospective studies the possible differences of this feature among settings. It is worth emphasizing the SCD-related worry as a characteristic that provides added value to the subjective impression of the self-cognitive performance, which could help to discriminate individuals with more risk to progression to AD.

Compared to MU subjects, the OHI sample showed better performances on global cognition, two executive tasks (automatic inhibition and abstract reasoning), and in recognition memory. In practical terms, these differences between samples are not clinically relevant, because the results did not reach the impaired range, since its normality is mandatory for the diagnosis of SCD. But lower scores in neuropsychological performance within the normal range in volunteers with SCD compared with controls, have been found to be predictive of future decline [2].

Our results are consistent with other studies that have found differences in neuropsychological performance according to the recruitment method. Brodaty et al. compared community versus clinical cohorts of cognitively normal subjects, finding that the population-based sample had lower MMSE score and poorer cognitive performance in memory, processing speed, attention, and language than a convenience sample [11]. Similarly, Blacker et al. found that poorer episodic memory and executive functions performance predict time to progress from normal cognition to MCI in a community volunteer-based sample [36]. These findings are relevant because cognitive performance on specific neuropsychological tests could predict the risk of progression from normal cognition to MCI.

In the present study, the percentage of APOE ɛ4 carriers was not different between samples, in contrast to what has been shown by van der Flier et al. [37] who obtained a higher frequency of ɛ4 allele among SCD subjects from a memory clinic sample when comparing them with a community-based cohort. However, this result could be related to the small sample size. Another explanation would be that the OHI sample is a midpoint between two types of convenience samples: volunteers and medical help seeking, and cannot be considered a community-based cohort. Thus, maybe in the same spectrum of recruitment method, there are no variations in the frequency of APOE ɛ4 carriers; but this should be replicated and confirmed in future prospective SCD studies.

We acknowledge some limitations of this study. First, as it has been mentioned before, the OHI sample comes from a unique recruitment method developed at Fundació ACE, which could be considered a convenience sample, where volunteers are invited to receive cognitive evaluation. We did not collect systematically objective measures of depressive symptoms and that leads to a suboptimal characterization of this key feature. On another hand, our sample is small, the analysis is singled center, retrospective, and cross-sectional, and these characteristics make it difficult to extrapolate our results. Nevertheless, given the observed differences found between settings, this analysis should be carried out in larger multicenter, prospective, and longitudinal studies, to investigate in depth these preliminary findings.

Bearing our results in mind, we conclude that there are differences in demographic and neuropsychological performance in subjects with SCD depending on the recruitment method, so the setting could influence the features of subjects with SCD with probable prognostic implications, as it has been demonstrated across the spectrum of the degenerative process from controls to to dementia due to AD. The lower performance on neuropsychological tests in the MU sample could suggest a higher enrichment of AD in the clinical cohort. This might indicate that the clinical setting is a type of recruitment that increases the chances of finding subjects with preclinical AD, which makes this method suitable for studying SCD due to AD, and for recruiting patients for secondary prevention trials. On the other hand, since health systems sometimes make it difficult to access subjects with subtle cognitive deficits, we present our experience with a community based approach with volunteers, which has allowed us to recruit a bigger number of individuals compared to the clinical referrals. Finally, these qualitative and quantitative issues should be taken into consideration in the design of observational studies and future clinical trials on SCD subjects.

Footnotes

ACKNOWLEDGMENTS

This study was supported in part by funds from Fundació ACE, Institut Catalá de Neurociències Aplicades. Fundació ACE researchers are indebted to Trinitat Port-Carbó and her family who are supporting Fundació ACE scientific programs. This institution thanks the Fundació ACE staff and patients, without whose contribution this work would not have been possible.

Authors’ disclosures available online ().

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