Subjective Memory Complaints Research Articles

Microstructural Correlates and Laterality Effect of Prospective Memory in Non-Demented Adults with Memory Complaints

Background: An increasing number of studies suggest the importance of prospective memory (ProM) due to its functional relevance and sensitivity to neuropathology. However, its relevant neural substrates have not been sufficiently explored. Objectives: The present study aimed to investigate the relationship between structural connectivity and both objective and subjective ProM measures in a group of non-demented people with subjective memory complaints, and to examine the potential of ProM measures to detect the difference between subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in the pre-dementia stage. Method: Thirty-sevennon-dementedparticipants aged above 50 years were recruited from an outpatient Neurology Clinic; 13 of them fulfilled the criteria of MCI and 24 of SCD. All subjects received comprehensive neuropsychological tests, including the adapted version of the Cambridge Prospective Memory Test, as well as the Taiwan version of the Prospective and Retrospective Memory Questionnaire. The diffusion tensor imaging technique with tract-based spatial statistics was applied to measure cerebral microstructural changes. Results: Time-based ProM performance was significantly correlated with microstructural integrity of the right superior longitudinal fasciculus, while the event-based one was associated with that of the left superior longitudinal fasciculus and the genu of the corpus callosum among all participants and in the SCD group. After controlling for age, the correlation remained significant between event-based ProM performance and the left superior longitudinal fasciculus among all participants and in the MCI group, as well as between event-based ProM performance and the genu among all participants. Although self-reported ProM failures in real life was associated with fiber disruption of the left superior longitudinal fasciculus among all participants and within the MCI group, an inverse relationship was also observed with that of the corpus callosum in the SCD group even after controlling for age. As compared to the SCD group, people with MCI performed significantly worse on time-based ProM tasks and reported more ProM failures in daily life. Conclusions: ProM was related to the integrity of interhemispheric commissural fibers and association fibers that connect the frontal lobe with posterior regions, with a task-specific laterality effect. Time-based ProM tasks and self-reported ProM questionnaire may be sensitive to early pathological cognitive deterioration, while the concomitant aging process and individual awareness level may respectively confound the results of evaluation.

Physical multimorbidity and subjective cognitive complaints among adults in the United Kingdom: a cross-sectional community-based study

Our goal was to examine the association between physical multimorbidity and subjective cognitive complaints (SCC) using UK nationally representative cross-sectional community-based data, and to quantify the extent to which a broad range of mainly psychological and behavioral factors explain this relationship. Data from the 2007 Adult Psychiatric Morbidity Survey were analyzed [N = 7399 adults, mean (SD) age 46.3 (18.6) years, 48.6% men]. Multimorbidity was defined as ≥2 physical diseases. SCC included two different cognitive constructs: subjective concentration and memory complaints. Multivariable logistic regression and mediation analyses were conducted. Multimorbidity was associated with higher prevalence of subjective concentration (30.7% vs. 17.3%) and memory complaints (42.8% vs. 22.9%) compared to no multimorbidity. In the regression model adjusted for sociodemographics, multimorbidity was associated with subjective concentration (OR = 2.58; 95% CI = 2.25–2.96) and memory complaints (OR = 2.34; 95% CI = 2.08–2.62). Sleep problems, stressful life events and any anxiety disorder explained 21–23%, 20–22% and 14–15% of the multimorbidity-SCC association, respectively. Multimorbidity and SCC are highly co-morbid. The utility of SCC screening in identifying individuals at high risk for future cognitive decline among individuals with multimorbidity should be assessed.

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints

ObjectiveGeriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. MethodsWe conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months. ResultsOf the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5–20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10–20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO. ConclusionsThe combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

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

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. To know whether aMCI patients with amyloid biomarkers (Aβ+) present greater SMCs as compared to those without amyloid biomarkers (Aβ-). 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 Aβ1-42 concentration or amyloid PET imaging. 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. Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD.

Visuospatial/executive abilities and mood affect the reliability of a subjective memory complaints measure.

Inconsistent results are reported so far in the literature on the relationship between subjective memory complaints (SMC) and objective memory performance. Mixed findings triggered the need to investigate whether other potential mediating variables, such as mood and non-memory domains, affect the relationship between SMC and memory performance. The present study aimed to contribute in clarifying the relation between subjective and objective memory considering the potential role of mood and visuospatial/executive functions. Six hundred and sixty Italian community-dwelling adults (52-91years old) were enrolled. Italian version of Montreal Cognitive Assessment Test (MoCA), Geriatric Depression Scale and Subjective Memory Complaints Questionnaire (SMCQ) were administered. Four subsamples were composed according to the following criteria: (a) participants with high visuospatial/executive function (VSE) score at MoCA and high mood; (b) participants with high VSE score and low mood; (c) participants with low VSE score and high mood and; (d) participants with low VSE score and low mood. Preliminarily, two confirmatory factor analysis have set the one-factor structure of SMCQ as the best fitting model. Diagnostic accuracy of the SMCQ in discriminating high and low memory score was assessed. ROC analyses confirmed that a low score in executive tasks was associated with poor reliability of the SMCQ. On the contrary, well-preserved executive functions and high mood levels ensured a good reliability of SMCQ in detecting memory problems. Although mood is a key mediator in the relationship between subjective and objective memory, preserving executive functions is essential for ensuring the accuracy of memory self-appraisal in adulthood and elderly.

Self-management practices associated with quality of life for adults with epilepsy.

Epilepsy self-management practices enhance a patient's competence and confidence in managing their chronic condition, which is assumed to lead to an improved quality of life (QoL). We analyzed the relationship between the Epilepsy Self-Management Scale (ESMS) responses and the Quality of Life in Epilepsy (QOLIE-31) scores. Baseline questionnaires from HOBSCOTCH, a self-management program for cognitive problems, were administered in four New England epilepsy centers on adults (n = 100) with epilepsy and subjective memory complaints. There was no correlation between overall self-management scores and overall quality-of-life scores; however, subscale analyses indicated that certain self-management practices were strongly correlated with the overall QOLIE-31 score. Specifically, improved ESMS lifestyle management was associated with an increased quality-of-life score (adjusted p < 0.01), while enhanced ESMS safety management practices were associated with a decreased overall quality-of-life score (adjusted p < 0.01). Our item-level analysis highlighted specific items within the ESMS safety management, ESMS lifestyle management, and ESMS information management subdomains that were significant predictors for QoL. Depression was also shown to be significantly correlated with the QOLIE-31 (p < 0.01). Our study suggests that an overemphasis on safety practices may negatively affect quality of life, while enhanced lifestyle management has positive effects. Furthermore, our finding that quality of life is greatly dependent on depressive symptoms underscores the importance of treating depression in epilepsy.

A Randomized Controlled Trial of Adherence to a 24-Month Home-Based Physical Activity Program and the Health Benefits for Older Adults at Risk of Alzheimer’s Disease: The AIBL Active-Study

Background:Previous studies have demonstrated that physical activity (PA) interventions can improve physical and cognitive outcomes in older adults, but most have been relatively short in duration (<1 year) with a few having specifically targeting individuals at risk of developing Alzheimer’s disease.Objective:To examine adherence and physical health outcomes in a 24-month home-based PA intervention in older adults at risk of Alzheimer’s disease.Methods:Participants 60 years and older with mild cognitive impairment (MCI) or subjective memory complaints (SMC) with at least 1 cerebrovascular risk factor recruited from The Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging (AIBL) were randomized to a PA or control group (n = 106). The control group continued with their usual lifestyle. The PA group received a 24-month home-based program with a target of 150 minutes/week of moderate PA and a behavioral intervention. Retention (participants remaining) and PA adherence (PA group only, percent PA completed to the PA prescribed) were determined at 6, 12, 18, and 24 months. Assessments at baseline, 6, 12, and 24 months included, PA; fitness; body composition and fat distribution. Key outcome measures were PA adherence and PA.Results:The 24-month retention rate (97.2%) and the median PA adherence 91.67% (Q1–Q3, 81.96, 100.00) were excellent. In the long-term the intervention group achieved significantly better improvements in PA levels, leg strength, fat mass and fat distribution compared to the control.Conclusion:This study demonstrates that in this target group, long-term PA adherence is achievable and has physical health benefits.

Validity of the French Prospective and Retrospective Memory Questionnaire (PRMQ) in healthy controls and in patients with no cognitive impairment, mild cognitive impairment and Alzheimer disease

ABSTRACTIntroduction: The Prospective and Retrospective Memory Questionnaire (PRMQ) is one of the most commonly used scales to assess both retrospective memory (RM) and prospective memory (PM) complaints. This study aimed to: 1/replicate the previous results concerning the PRMQ latent structure in a French version and 2/provide its psychometric properties in a normal and clinical population.Method: This observational study included 488 participants divided into five subgroups. A sample of 168 healthy participants (no memory consultation sought), served as controls. Patients were recruited in a memory clinic: 98 “functional” patients (subjective memory complaints but no memory impairment), 83 amnestic-Mild Cognitive Impairment (a-MCI), 82 non-amnestic-MCI (na-MCI) and 57 Alzheimer Disease (AD) patients. Structure, validity, consistency, reliabilitiy and reproducibility of the PRMQ were calculated. Novelty, Area Under the Receiver-Operating Characteristics (AUROC) curve, was used to determine the optimal cut-off, to distinguish “functional” patients from control participants.Results: The optimal fit model of the French PMRQ was not a tri but a bi-partite model, with a RM and a PM subscale. The convergent validity showed significant correlation with cognitive difficulties (r = .82 and .78, respectively), anxiety (r = .44 and .48, respectively) and depression (r = .23) scales. Cronbach’s alpha was good (α = .79 and .88), as well as the reproducibility (r = .71 and .80). The interaction [Subgroups of participants x PMRQ Subscales] was significant [F(4, 483) = 11.46; p < .001]. The power discrimination was adequate (AUROC = .71 and .74) for detecting “functional” patients compared with controls, in particular for the PM subscale (sensitivity 66.6%, specificity 77.4%).Conclusions: The PMRQ, with minor changes, was validated in its French form with satisfactory psychometric qualities. This self-rating tool appears useful for identifying significant memory complaints in a normal population and may also be helpful in discriminating between functional/na-MCI and a-MCI/AD patients.

Handedness, Grip Strength, and Memory Function: Considerations by Biological Sex.

Background and Objective: The objective of this study was to evaluate the potential independent and interactive effects of handedness and grip strength on episodic memory function, and whether biological sex moderated these relationships. Materials and Methods: 162 young adults (Mage = 20.7 years) completed a series of memory assessments including a subjective memory complaint evaluation and several objective measures of memory. Handedness (i.e., left-hand dominant, inconsistent handedness (ICH), and right-hand dominant) was evaluated using the Edinburgh Handedness Inventory. Handgrip strength was determined from a handgrip dynamometer. Results: When compared to ICH individuals, retrospective memory scores were statistically significantly worse for left-handed (p = 0.02) and right-handed (p = 0.03) individuals. Higher grip strength was statistically significantly associated with fewer retrospective memory complaints (b = 0.10, 95% CI: 0.01, 0.19, p = 0.04). Conclusions: The present study provides some suggestive evidence that ICH (inconsistent handedness) and greater grip strength are associated with fewer retrospective memory complaints. However, we did not observe any evidence of an interaction effect of handedness and grip strength on memory, and similarly, biological sex did not interact with these parameters to influence memory.

A-51 A Novel Memory Catastrophizing Scale

Abstract Objective A weak relationship exists between subjective memory complaints and performance on objective measures of learning and memory. A memory catastrophizing scale may explain this relationship. Our objective is to preliminarily explore a scale which assesses catastrophizing. Method The sample consisted of 46 patients (21 normal profiles, 25 mild cognitive impairment; mean age 56.1 ± 15.4) in a community-based neurology clinic. Each patient completed a clinical interview and comprehensive neuropsychological battery. The California Verbal Learning Test II (CVLT-II) was used to assess memory; the Beck Depression Inventory and Beck Anxiety Inventory were used to assess depressive and anxiety symptoms; a novel Memory Catastrophizing Scale (MCS) was used to assess subjective memory. Results A reliability analysis revealed internal consistency throughout the MCS (Cronbach’s alpha = .958). A bivariate correlation revealed that memory catastrophizing was significantly positively correlated with depressive (r = 0.623, p &lt; 0.01) and anxiety (r = 0.433, p &lt; 0.01) symptomology. Bivariate correlations demonstrated significant positive correlations between subjective memory complaints and memory (CVLT-II SDFR r = 0.502, p &lt; .05; SDCR r = 0.434, p = 0.05; LDCR r = 0.512, p &lt; .05) only among NP patients. The mean MCS score was 26 (±17), with a median of 17, a skewness of 0.40 and kurtosis of -0.77. Conclusion Our results support past research suggesting that there is a weak relationship between subjective and objective memory performances. Catastrophizing as a concept may explain the relationship between mood and performance on testing, especially amongst individuals without a known neurological pathology seeking treatment at a community-based neurological clinic.

C-23 Impact of Social Support on Cognitive Vascular Risk Factors in Latino Older Adults

Abstract Objective Central Americans have a cardiovascular disease (CVD) health advantage, as they are half as likely to carry CVD as European Americans, despite having an equivalent degree of vascular risk factors (VRFs). We examined the impact of social support on this paradox and the relationship to cognitive decrements among Costa Rican older adults. Methods We identified predictors of the CVD health advantage (VRFs in the absence of CVD: Heart Attack, MI, Stroke). Hypertension (HTN) and CVD were coded as present or absent based on medical history. Of 315 participants, 146 (46%) had HTN but no CVD, 59 (19%) had CVD, and 110 had neither HTN nor CVD. To estimate ROC curves, we applied canonical discriminant analysis to item groups based on the discipline cluster. The discriminant analysis identified items that maximally differentiated the diagnostic groups in a step-wise fashion. Results Social support and social engagement were stronger predictors of the health advantage than subjective memory complaints. Social Support was a reliable indicator of CVD health advantage (accuracy = 93%, sensitivity = 93%, specificity = 89%). Social Engagement was a reliable discriminator of diagnostic groups (accuracy = 84%, sensitivity = 88%, specificity =75%) versus subjective memory complaints (accuracy = 79%, sensitivity of 82%, specificity of 74%). Conclusion Our exploratory analyses suggest that social support is an important predictor of living with VRFs but not developing CVD. Current studies are underway to examine the contribution of these risk factors to the development of dementia and cognitive impairment to maximize cost-effective interventions.

Association between childhood socioeconomic status and subjective memory complaints among older adults: results from the Japan Gerontological Evaluation Study 2010.

Subjective memory complaints (SMC) have been suggested as an early marker of mild cognitive impairment and dementia. However, there is a paucity of evidence on the effects of early life conditions on the development of SMC in old age. This study is aimed at investigating the association between childhood socioeconomic status (SES) and SMC in community-dwelling older adults. We used the data of the Japan Gerontological Evaluation Study, a population-based cohort study of people aged 65 years or older enrolled from 28 municipalities across Japan. Childhood SES and SMC in everyday life were assessed from the self-report questionnaire administered in 2010 (n = 16,184). Poisson regression was performed to determine their association, adjusted for potential confounders and life-course mediators and examined cohort effects. We identified SMC in 47.4% of the participants. After adjusting for sex, age, and number of siblings, low and middle childhood SES were associated with 29% (prevalence ratio [PR]: 1.29, 95% confidence interval [CI]: 1.22, 1.36) and 10% higher prevalence of SMC (PR: 1.10, 95%CI: 1.04, 1.17), respectively, compared with high childhood SES (p for trend <.001). The interaction terms between childhood SES and age groups were not statistically significant. Childhood SES is significantly associated with SMC among community-dwelling older adults. Efforts to minimize childhood poverty may diminish or delay the onset of SMC and dementia in later life.

Efficacy and Safety of Electroconvulsive Therapy in Adolescents: A Retrospective Chart Review Study From Turkey.

The aim of this study was to report the efficacy and safety of electroconvulsive therapy (ECT) in manic, depressed, psychotic, and catatonic adolescent patients. Medical records of 78 adolescents who had received ECT in Department of Psychiatry, Gaziantep University Medical Faculty, during 2011 to 2017 were reviewed. Sixty-two subjects in this sample were identified to have complete records and met the study inclusion criteria. The mean ± SD age of subjects was 17.11 ± 1.04 years and female sex was 53.2% (n = 33). Primary the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision or the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnoses were bipolar mood disorders (n = 33, 53.2%), major depressive disorder (n = 16, 25.8%), schizophrenia (n = 8, 12.9%), and schizoaffective disorders (n = 5, 8.1%). Electroconvulsive therapy was significantly effective in treating manic, depressive, psychotic, and catatonia symptoms as evidenced by significant differences in pretreatment and posttreatment scores in outcome measures including Hamilton Depression Rating Scale, Young Mania Rating Scale, Positive and Negative Syndrome Scale, and Clinical Global Impression-Severity Scale (P < 0.001). Presence of comorbidity adversely affected treatment response (P = 0.001). However, ECT was also effective in those with comorbid diagnoses (P < 0.001). Depressive symptoms in patients with bipolar depression responded better than those with unipolar depression (P = 0.012). Electroconvulsive therapy was generally safe with subjective memory complaints (85%), headache (69%), and prolonged seizure (8%) as the reported adverse effects possibly related to ECT. Four subjects (6%) developed a manic switch during ECT. Electroconvulsive therapy is an effective and a safe treatment option in adolescent patients with severe and resistant psychopathology. Although comorbidity may decrease treatment response, ECT seems to be effective even in the presence of multiple psychiatric diagnoses.

Instrumental Activities of Daily Living: The Processes Involved in and Performance of These Activities by Japanese Community-Dwelling Older Adults with Subjective Memory Complaints.

Subjective memory complaints (SMCs) may predict the onset of dementia. The purpose of this study was to clarify characteristics of performance of activities of daily living (ADL) for older adults with SMCs and to offer support options that enable them to maintain their community-based lifestyle. A self-administered questionnaire was sent to 2000 randomly selected members of CO-OP Kagoshima, and 621 responded. 270 responders answered all questions were categorized into SMC (+) group and SMC (−) group (n = 133). Participants were evaluated the Process Analysis of Daily Activity for Dementia. A 2-sample t-test or the Chi-square test were used to compare the averages of continuous variables or the proportions of categorical variables. The results showed the SMC (+) group ranked significantly lower in ability to use the telephone, shop, cook, do housekeeping, manage finances, and manage medications compared with the SMC (−) group. In addition, the SMC (+) group was significantly less independent than the SMC (−) group in many processes requiring the use of tools, operation of machines, management of goods, selection of tools, and monitoring. To enable continued independence of older adults’ experiencing SMCs, it may be important to analyze their performance of ADL and to develop plans for supporting their strengths.

Effects of multiple training modalities in the elderly with subjective memory complaints: A pilot study.

Background:This study investigated the effects of multiple training modalities (MTM) on senior fitness and neuropsychiatric function in the elderly with subjective memory complaints (SMC).Methods:This study was conducted in 24 elderly subjects with Clinical Dementia Rating (CDR) score of 0 and instrument of ascertainment of dementia 8 (AD8) score of <2. The participants were classified into SMC (n = 7) and non-SMC (n = 17).All were assigned to receive multiple training modalities (1 hour for each training: physical fitness activities, calligraphy or drawing, and meditation) twice a week over a 16-week period.A series of senior fitness test, and neuropsychiatric tests, namely the Traditional Chinese version Mini-Mental Status Examination (MMSE), Cognitive Assessment Screening Instrument (CASI), and the Center for Epidemiologic Studies Depression Scale (CESD), were conducted before and after the intervention. We compared the differences of pre/posttest-MTM and SMC/non-SMC in senior fitness and the neuropsychological tests.Results:There was no significant difference between SMC and non-SMC groups in demographic characteristics. MTM showed significant improvement in senior fitness and CESD, but not in CASI and MMSE. Significant change in recent memory subscale of CASI was only observed in SMC group, whereas improvement of partial senior fitness and CESD were observed in both groups.Conclusion:MTM had effects in enhancing senior fitness and improving depressive syndromes in the elderly. MTM contributed to greater improvement in recent memory function in the SMC group than in the non-SMC group.

IMPACT OF MEMORY TRAINING WITH METAMEMORY CONCEPT IN THE ELDERLY WITH SUBJECTIVE MEMORY COMPLAINTS

Understanding how memory works and accurately monitoring the memory processes enable the appropriate planning and execution of the memory strategy. In this study, the effects of the multi-strategic memory training based on the metamemory concept were tested in older adults with subjective memory complaint using both behavioral and MRI approaches. Two hundred one community-dwelling elders with subjective memory complaints participated in the study and were randomized to multi-strategic memory training of 10 weekly 90 minute-sessions based on the metamemory concept or usual care. Among them, 49 (39 from the training group and 10 from the control group) were randomly selected for brain MRI imaging. The training group showed a significantly higher increase in delayed free recall, categorical fluency and Boston naming test. In the brain structure analyses, the mean diffusivity of the bundles of axon tracts passing from the frontal lobe to the posterior end of the lateral sulcus was decreased more in the training group. In addition, the cortical thickness of the left rectal gyrus in the frontal cortex was increased more in the training group than in the control group. These Results indicate that the training program for understanding and monitoring memory has vital and positive impacts on enhancing elders’ cognitive performance. Improved white matter integrity in the anterior and posterior cerebrum and increased cortical thickness of prefrontal region, which are related to metacognition, possibly suggest that the effects of the metamemory training would be induced via the enhancement of cognitive control.

SEXUAL DIMORPHISM IN PLASMA BETA-SECRETASE 1 CONCENTRATIONS IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR AD: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

The development of effective disease-modifying treatments for early Alzheimer's disease (AD) and targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted requires biomarker-drug co-development strategies, including the validation and qualification of accessible and non-invasive biological markers for different contexts of use. Cross-sectional and longitudinal studies demonstrated that plasma and cerebrospinal fluid (CSF) concentrations of BACE1 closely correlate with each other. We conducted both cross-sectional and longitudinal explorative studies in a cohort of individuals with subjective memory complaint (SMC), a condition at risk for AD, to investigate whether key biological factors such as sex, APOE ε4allele, and age affect plasma BACE1 concentrations. SMC individuals were recruited from the “INveStIGation of AlzHeimer's PredicTors in Subjective Memory Complainers” (INSIGHT-preAD) study, a university-based cohort which is part of the Alzheimer Precision Medicine Initiative (APMI) and its Cohort Program (APMI-CP). In the cross-sectional analysis, we found that baseline plasma BACE1 concentrations were highly significantly increased in females compared to males (p<0.001). Women showed a highly significantly increased plasma BACE1 concentrations compared to men, at all the three investigated time intervals (p<0.001). No difference regarding the longitudinal trajectories of plasma BACE1 concentrations was found between women and men. There was no significant effect of age and APOE ε4carrier status neither on overall BACE1 concentrations nor on BACE1 concentrations evolution. There was a highly significant decrease in plasma BACE1 concentrations in the whole sample of SMC individuals over time (p<0.001). We did not find any significant impact of two-way interactions between age and sex, age and APOE ε4 allele, sex and APOE ε4 allele on BACE1 plasma concentrations either at baseline or longitudinally. Thus, we demonstrate that the impact of a sexual-dimorphism on plasma BACE1 concentrations is irrespective of age and time. Evidence of the potential impact of a sexual dimorphism on the concentration and activity of BACE1 may be a relevant missing design component contributing to the failure of negative clinical BACE1 inhibitor therapy trial outcomes. Our results indicate that the impact of a sexual dimorphism on plasma BACE1 should be considered in further biomarker validation and qualification studies and in clinical BACE1 trials.

SIMULATED COGNITIVE TRAJECTORIES IN PATIENTS WITH/WITHOUT HISTORY OF STROKE WHO ARE AT RISK OF DEVELOPING ALZHEIMER’S DISEASE USING AD ACE

There is substantial evidence in the literature that cerebrovascular factors such as history of stroke have a cumulative effect on Alzheimer's disease (AD) development and are associated/correlated with an increased risk of degenerative AD pathology and cognition decline. The AD Archimedes Condition-Event simulator (AD ACE) employs a set of AD disease equations to predict the progression of disease over time based on change in AD biomarkers including measures of amyloid PET (AV45) and tau (CSF t-tau) levels and their connections to clinical presentation of AD, including cognition and behavioral scales. History of stroke, however, was not included as a predictor in the AD ACE disease equations. We used AD ACE to compare patients with history of stroke versus those without and studied how potential effect of stroke may be mediated through other clinical AD biomarkers on disease progression over time. We simulated the disease progression of cognitively normal (CN) individuals and those with subjective memory complaint (SMC) in the ADNI1 dataset. We analyzed the change in two cognitive scales (MMSE, CDRSB) over 10 years between two patient subgroups based on their history of stroke at baseline. A total of 149 CN/SMC patients were identified in ADNI1 for inclusion in this study (18 with Stroke History, 131 without Stroke History). The two patient subgroups were very similar in terms of their mean age and other baseline biomarkers and cognition scales. The simulated trajectories showed faster cognitive decline (ΔCDRSB=1.3 and ΔMMSE=2) and an odds ratio of 1.37 for incidence of dementia for the subgroup with vs. without history of stroke over 10 years which is aligned with reported outcomes in the literature including a recent analysis of the patients from the Rotterdam Study. A simulation using the AD ACE equations, which do not explicitly include stroke history, projects faster cognitive decline and greater risk of dementia for patients with history of stroke. This suggests the effects of stroke on cognitive decline may be mediated through other clinical AD biomarkers.

P2‐451: RECOGNITION MEMORY PERFORMANCE AS A COGNITIVE MARKER OF PRODROMAL ALZHEIMER'S DISEASE

The utility of recognition memory indices for identifying persons with biological evidence of Alzheimer's disease is unclear, as studies have diagnosed mild cognitive impairment due to AD using clinical criteria rather than CSF measures of central amyloidosis and tauopathy. We evaluated whether recognition memory indices of discriminability and response bias derived from signal detection theory differentiate persons with amnestic MCI with positive CSF evidence of AD (prodromal AD) vs. non-prodromal amnestic MCI. 133 participants in the VAScular ContribUtors to ProdromaL AlzheimeR's disease (VASCULAR) study were clinically diagnosed at their screening evaluations with amnestic MCI using ADNI criteria including a subjective memory complaint, impaired performance on Logical Memory, 0.5 on the CDR memory box, and relatively preserved IADLs (FAQ). At their baseline visit, they received the Hopkins Verbal Learning Test-Revised which assesses learning and recall of 12 words, followed by delayed recall and recognition (12 targets, 12 foils). Participants also underwent LPs, and AD biomarkers were measured (ALZBIO3) in Dr. Leslie Shaw's lab (U.Penn). Participants were classified as prodromal AD if they had a tau/amyloid ratio of ≥0.45 using previously published cutoffs (Shaw et al., Alzheimers Dement 10:698-705, 2018). 34 (26%) MCI participants had prodromal AD. They were significantly older (72.2±6.8 years) and had lower MoCA scores (20.9±2.6 points) than the non-prodromal group (64.6±8.5 years; 22.4±2.8 points), but did not differ in education (15.8±2.9 years vs. 15.5±3.1 years). ANCOVAs controlling for age and MoCA scores demonstrated differences in hits (Prodromal: 9.5±2.9, non-Prodromal: 11.2±1.2, p=.004) but not false alarms (Prodromal: 2.1±1.9; non-Prodromal 1.3±1.4, p=.14). A discriminability measure (d’) which simultaneously considers hits and false alarms was lower in the prodromal (2.0±1.9) vs. non-prodromal (5.1±2.2) groups, p<.001. A cutoff of 5.0 had 71% sensitivity and 70% specificity, with 93/133 participants correctly classified. There were no significant differences in response bias (Prodromal: .12±1.3; non-Prodromal: −.42±1.2, p=.10). Individuals with amnestic MCI due to prodromal AD are less accurate in distinguishing targets from foils. Discriminability may serve as a marker of prodromal AD and could be utilized with other memory indices to facilitate differential diagnosis of amnestic MCI due to AD vs. non-AD etiologies.

경도인지장애 환자의 주관적 기억장애, 우울 및 집행기능이 일상생활 수행능력에 미치는 영향

Purpose: This study aimed to examine the effects of subjective memory complaints, depression and cognitive function on performance of activities of daily living (ADL) in individuals with mild cognitive impairment (MCI). Methods: A total sample consisted of 250 MCI patients diagnosed within one year. All participants were assessed with a battery of standardized neuropsychological tests, self-report measures of subjective memory complaints and depression, and performance of basic and instrumental ADL. Correlational and multiple linear regression analyses were conducted to identify the factors associated with performance of basic and instrumental ADL, respectively. Results: Executive function and depression explained 9.4% of the variance in basic ADL. Reduced executive function and greater depressed mood were associated with worse performance on basic ADL. Executive function, subjective memory complaints, and time since onset of cognitive symptoms accounted for 22.2% of the variance in instrumental ADL in individuals with MCI. Lower executive function (t=-2.02, p=.044), greater memory complaints (t=5.36, p.001), and longer periods of experiencing cognitive symptoms (t=2.24, p=.026) were associated with worse instrumental ADL performance. Conclusion: These results may help healthcare professionals develop interventions to improve cognitive outcomes with better understanding of the relationship among cognition, mood, and behavioral performance in individuals with MCI.