The Usefulness of 18F-FDG PET to Differentiate Subtypes of Dementia: The Systematic Review and Meta-Analysis.

Background and Purpose: Dementia subtypes, including Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), pose diagnostic challenges. This review examines the effectiveness of 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) in differentiating these subtypes for precise treatment and management. Methods: A systematic review following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was conducted using databases like PubMed and Embase to identify studies on the diagnostic utility of 18F-FDG PET in dementia. The search included studies up to November 16, 2022, focusing on peer-reviewed journals and applying the gold-standard clinical diagnosis for dementia subtypes. Results: From 12,815 articles, 14 were selected for final analysis. For AD versus FTD, the sensitivity was 0.96 (95% confidence interval [CI], 0.88-0.98) and specificity was 0.84 (95% CI, 0.70-0.92). In the case of AD versus DLB, 18F-FDG PET showed a sensitivity of 0.93 (95% CI 0.88-0.98) and specificity of 0.92 (95% CI, 0.70-0.92). Lastly, when differentiating AD from non-AD dementias, the sensitivity was 0.86 (95% CI, 0.80-0.91) and the specificity was 0.88 (95% CI, 0.80-0.91). The studies mostly used case-control designs with visual and quantitative assessments. Conclusions: 18F-FDG PET exhibits high sensitivity and specificity in differentiating dementia subtypes, particularly AD, FTD, and DLB. This method, while not a standalone diagnostic tool, significantly enhances diagnostic accuracy in uncertain cases, complementing clinical assessments and structural imaging.

Development and preliminary validation of a virtual reality memory test for assessing visuospatial memory.

Background: Visuospatial memory impairment is a common symptom of Alzheimer's disease; however, conventional visuospatial memory tests are insufficient to fully reflect visuospatial memory impairment in daily life. Methods: To address patients' difficulties in locating and recalling misplaced objects, we introduced a novel visuospatial memory test, the Hidden Objects Test (HOT), conducted in a virtual environment. We categorized HOT scores into prospective memory, item free-recall, place free-recall, item recognition, and place-item matching scores. To validate the VR memory test, we compared HOT scores among individuals with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and normal controls (NC), and also compared these scores with those of conventional neuropsychological tests. We tracked the participants' movement paths in the virtual environment and assessed basic features, such as total distance, duration, and speed. Additionally, we performed walking trajectory pattern mining such as outlier and stay-point detection. Results: We designed and implemented the HOT to simulate a house's living room and assess participants' ability to locate hidden objects. Our preliminary results showed that the total HOT score differed among 17 patients with AD, 14 with aMCI, and 15 NC (p < 0.001). The total HOT score correlated positively with conventional memory test scores (p < 0.001). Walking trajectories showed that patients with AD and aMCI wandered rather than going straight to the hidden objects. In terms of basic features, the total duration was significantly greater in AD than in NC (p = 0.008). In terms of trajectory pattern mining, the number of outliers, which were over 95% of the estimated trajectory, was significantly higher in AD than in NC (p = 0.002). The number of stay points, an index in which participants stayed in the same position for more than 2 s, was significantly higher in patients with AD and aMCI compared with NC (AD vs. NC: p = 0.003, aMCI vs. NC: p = 0.019). Conclusion: The HOT simulating real life showed potential as an ecologically valid test for assessing visuospatial memory function in daily life. Walking trajectory analysis suggested that patients with AD and aMCI wandered rather than going straight toward the hidden objects.

Efficacy of smartphone application-based multi-domain cognitive training in older adults without dementia.

Background: As the population ages and the prevalence of dementia increases, there is a growing emphasis on the importance of cognitive training to prevent dementia. A smartphone application-based cognitive training software program, BeauBrain Trainer (BBT), has been developed to provide better access to cognitive training for older adults. Numerous studies have revealed the effectiveness of cognitive training using a cognitive assessment tool. However, relatively few studies have evaluated brain activation using brain imaging as a result of improved cognitive function. Methods: All participants were required to download the BBT, an Android-based application for cognitive training, onto their own smartphone or tablet computer and to engage in cognitive training at home. Older adults without dementia were enrolled in this study, including 51 participants in the intervention group and 50 participants in the control group. The BBT comprised a set of 12 cognitive tasks, including two tasks in each of the following six cognitive domains: attention, language, calculation, visuospatial function, memory, and frontal/executive function. Each cognitive task was divided into four blocks based on its level of difficulty. A 16-week cognitive training was designed to carry out cognitive tasks using a total of 48 blocks (12 tasks × 4 levels) for at least 1.5 h per day, 5 days per week. All participants in the intervention group were given BBT tasks that gradually increased in difficulty level, which they submitted through a smartphone application daily for 16 weeks. The researchers monitored the participants' task performance records on the website and encouraged participants to engage in cognitive training through regular contact. This study was conducted to investigate the improvement in cognitive function and the activation pattern of the frontal cortex in older adults participating in smartphone application-based cognitive training. The cognitive assessment tool was the BeauBrain cognitive screening test (CST), a tablet-based computerized cognitive screening test. The activation pattern of the frontal cortex was measured using functional near-infrared spectroscopy (fNIRS). Additionally, this study aimed to determine the positive effects of cognitive training on everyday functioning and psychological states using a questionnaire. Results: Of 101 participants, 85 older adults without dementia (84.1%) who completed the study protocol were included in the statistical analysis. There were 41 participants (80.3%) in the intervention group and 44 participants (88.0%) in the control group. A two-way repeated-measures analysis of variance (ANOVA) was used to compare the cognitive scores over a 16-week period between the intervention and control groups. According to the CST results, the intervention group exhibited a statistically significant increase in the language subtest scores, specifically the phonemic word fluency test, compared to those of the control group. The fNIRS results revealed greater activation in the dorsolateral prefrontal cortex during the STROOP incongruent task in the intervention group than did the control group. However, the effectiveness of cognitive training was not observed across a variety of rating scales, including everyday functioning, depression, self-efficacy, attention, and subjective memory complaints. Conclusion: This study revealed that a smartphone-based cognitive training application led to improvements in phonemic generative naming ability and activation of the prefrontal cortex in older adults without dementia. This study is meaningful because it confirmed that cognitive training is partially effective in enhancing frontal lobe function. It also provided information on the brain mechanisms related to the effects of cognitive training using fNIRS.

Classification and prediction of cognitive trajectories of cognitively unimpaired individuals.

Objectives: Efforts to prevent Alzheimer's disease (AD) would benefit from identifying cognitively unimpaired (CU) individuals who are liable to progress to cognitive impairment. Therefore, we aimed to develop a model to predict cognitive decline among CU individuals in two independent cohorts. Methods: A total of 407 CU individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 285 CU individuals from the Samsung Medical Center (SMC) were recruited in this study. We assessed cognitive outcomes by using neuropsychological composite scores in the ADNI and SMC cohorts. We performed latent growth mixture modeling and developed the predictive model. Results: Growth mixture modeling identified 13.8 and 13.0% of CU individuals in the ADNI and SMC cohorts, respectively, as the "declining group." In the ADNI cohort, multivariable logistic regression modeling showed that increased amyloid-ß (Aß) uptake (ß [SE]: 4.852 [0.862], p < 0.001), low baseline cognitive composite scores (ß [SE]: -0.274 [0.070], p < 0.001), and reduced hippocampal volume (ß [SE]: -0.952 [0.302], p = 0.002) were predictive of cognitive decline. In the SMC cohort, increased Aß uptake (ß [SE]: 2.007 [0.549], p < 0.001) and low baseline cognitive composite scores (ß [SE]: -4.464 [0.758], p < 0.001) predicted cognitive decline. Finally, predictive models of cognitive decline showed good to excellent discrimination and calibration capabilities (C-statistic = 0.85 for the ADNI model and 0.94 for the SMC model). Conclusion: Our study provides novel insights into the cognitive trajectories of CU individuals. Furthermore, the predictive model can facilitate the classification of CU individuals in future primary prevention trials.

Eye-Tracking Metrics for Figure-Copying Processes in Early- vs. Late-Onset Alzheimer's Disease.

Visuospatial dysfunction is a common symptom in patients with Alzheimer's disease (AD). To more focus on copying processes rather than on finally completed figures, we conceptually split the copying processes into three stages: visuoperceptual function, visuoconstructional function, and working memory function. We constructed perceptual and working spaces to investigate the different stages of copying, and then, we compared the number and duration of fixations and saccades and the number of switches across the two spaces. We used eye-tracking glasses to assess eye-tracking metrics in patients with early-onset AD (EOAD), patients with late-onset AD (LOAD), and normal control (NC) participants while they copied the simplified Rey-Osterrieth complex figure test (RCFT). Regarding eye metrics on the perceptual space, the number and duration of fixations were greater in both groups of patients with AD than in the NC participants group (number: EOAD vs. NC: p < 0.001, LOAD vs. NC: p = 0. 003/ duration: EOAD vs. NC: p < 0.001, LOAD vs. NC: p < 0.001). On the working space, the number and duration of fixations were greater in the patients with EOAD than in the patients with LOAD and NC participants (number: EOAD vs. LOAD: p = 0. 007, EOAD vs. NC: p = 0. 001/duration: EOAD vs. LOAD: p = 0. 008, EOAD vs. NC: p = 0. 002). The number of saccades and switching was higher in patients with EOAD than in NC participants (p < 0.001). The eye-tracking metrics from the simplified RCFT correlated with the neuropsychological test scores. Patients with EOAD and LOAD achieved the same level of performance at the simplified and original RCFT scores. However, patients with EOAD than LOAD showed a greater number and duration of fixations on the working space and more frequent switching between the perceptual and working spaces, which may reflect more cognitive efforts to achieve the same level of performance.

Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer's dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD's diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

Annual Incidence of Dementia from 2003 to 2018 in Metropolitan Seoul, Korea: A Population-Based Study.

National dementia plans were applied in dementia support centers established in Seoul, Korea between 2007 and 2009. However, the annual incidence rates of dementia in Seoul have not been reported. We investigated this annual incidence and the characteristics of incident cases from 2003 to 2018. The customized research database of the Korean National Health Insurance Services was used. The annual crude and age-standardized incidence of dementia patients and their characteristics were analyzed. This study analyzed 108,596 incident dementia cases aged ≥60 years. The incidence rate increased from 2003 to 2011, including a rapid increment from 2007 to 2011. From 2011 to 2018, the crude (age-standardized) incidence per 105 person-years decreased from 641.51 (577.12) to 448.26 (361.23). The proportion of incident dementia cases was highest in the highest income group every year. However, the proportion of incident dementia cases in the lowest income group increased from 10.4% in 2003 to 25.8% in 2011. The annual incidence rate of dementia showed a sharp increase immediately after 2007, the year dementia support centers began to be introduced, and then stabilized after 2011. The characteristics of incident dementia cases have changed, including the proportion in the low-income group.

Longitudinal amyloid cognitive composite in preclinical Alzheimer's disease.

BACKGROUND AND PURPOSE: Previous studies have developed several cognitive composites in preclinical Alzheimer disease (AD). However, more sensitive measures to track cognitive changes and therapeutic efficacy in preclinical AD are needed considering the diverse sociocultural and linguistic backgrounds. This study developed a composite score that can sensitively detect the amyloid-ß (Aß)-related cognitive trajectory of preclinical AD using Korean data. METHODS: A total of 196 cognitively normal participants who underwent amyloid positron emission tomography were followed-up with neuropsychological assessments. We developed the Longitudinal Amyloid Cognitive Composite in Preclinical AD (LACPA) using the linear mixed-effects model (LMM) and z scores. The LMM was also used to investigate the longitudinal sensitivity of the LACPA and the association between time-varying brain atrophy and the LACPA. RESULTS: Considering the group-time interaction effects of each subtest, the Seoul Verbal Learning Test-Elderly version immediate recall/delayed recall/recognition, the Korean Trail Making Test B Time, and the Korean Mini-Mental State Examination were selected as components of the LACPA. The LACPA exhibited a significant group-time interaction effect between the Aß+ and Aß- groups (t = -3.288, p = 0.001). Associations between time-varying LACPA and brain atrophy were found in the bilateral medial temporal, right lateral parietal, and right lateral frontal regions, and hippocampal volume. CONCLUSIONS: The LACPA may contribute to reduction in time and financial burden when monitoring Aß-related cognitive decline and therapeutic efficacy of the disease-modifying agents specifically targeting Aß in secondary prevention trials.

Cortical neuroanatomical changes related to specific neuropsychological deficits in subcortical vascular cognitive impairment.

OBJECTIVE: Neuropsychological test-specific neural substrates in subcortical vascular cognitive impairment (SVCI) are expected to differ from those in Alzheimer's disease-related cognitive impairment (ADCI) but the details are unclear. To determine neural substrates related to cerebral small vessel disease, we investigated the correlations between cognitive dysfunctions measured by standardized neuropsychological tests and cortical thickness in a large sample of participants with amyloid negative (Aß (-)) SVCI. METHODS: One hundred ninety-eight participants with Aß (-) SVCI were recruited from the memory clinic between November 2007 to August 2018. To acquire neural substrates, we performed linear regression using the scores of each neuropsychological test as a predictor, cortical thickness as an outcome, and age, sex, education years, intracranial volume and white matter hyperintensity (WMH) as confounders. RESULTS: Poor performances in each neuropsychological test were associated with cortical atrophy in certain brain regions regardless of WMH. Especially, not the medial temporal but the frontal and posterior cingulate regions with cortical atrophy were mainly associated with memory impairment. Poor performance in animal fluency was more likely to be associated with cortical atrophy in the left hemisphere, while poor performance in the visuospatial memory test was more likely to be associated with cortical atrophy in the right hemisphere. CONCLUSIONS: Our findings suggested that cortical atrophy was an important factor of cognitive impairment in Aß (-) SVCI regardless of WMH. Furthermore, our findings might give clinicians a better understanding of specific neural substrates of neuropsychological deficits in patients with SVCI.

Differential effects of risk factors on the cognitive trajectory of early- and late-onset Alzheimer's disease.

BACKGROUND: Although few studies have shown that risk factors for Alzheimer's disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer's disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD. METHODS: We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. RESULTS: APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. CONCLUSIONS: Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.

Cognitive trajectories of patients with focal ß-amyloid deposition.

BACKGROUND: The presence of ß-amyloid (Aß) in the brain can be identified using amyloid PET. In clinical practice, the amyloid PET is interpreted based on dichotomous visual rating, which renders focal Aß accumulation be read as positive for Aß. However, the prognosis of patients with focal Aß deposition is not well established. Thus, we investigated cognitive trajectories of patients with focal Aß deposition. METHODS: We followed up 240 participants (112 cognitively unimpaired [CU], 78 amnestic mild cognitive impairment [aMCI], and 50 Alzheimer's disease (AD) dementia [ADD]) for 2 years from 9 referral centers in South Korea. Participants were assessed with neuropsychological tests and 18F-flutemetamol (FMM) positron emission tomography (PET). Ten regions (frontal, precuneus/posterior cingulate (PPC), lateral temporal, parietal, and striatum of each hemisphere) were visually examined in the FMM scan, and participants were divided into three groups: No-FMM, Focal-FMM (FMM uptake in 1-9 regions), and Diffuse-FMM. We used mixed-effects model to investigate the speed of cognitive decline in the Focal-FMM group according to the cognitive level, extent, and location of Aß involvement, in comparison with the No- or Diffuse-FMM group. RESULTS: Forty-five of 240 (18.8%) individuals were categorized as Focal-FMM. The rate of cognitive decline in the Focal-FMM group was faster than the No-FMM group (especially in the CU and aMCI stage) and slower than the Diffuse-FMM group (in particular in the CU stage). Within the Focal-FMM group, participants with FMM uptake to a larger extent (7-9 regions) showed faster cognitive decline compared to those with uptake to a smaller extent (1-3 or 4-6 regions). The Focal-FMM group was found to have faster cognitive decline in comparison with the No-FMM when there was uptake in the PPC, striatum, and frontal cortex. CONCLUSIONS: When predicting cognitive decline of patients with focal Aß deposition, the patients' cognitive level, extent, and location of the focal involvement are important.

Effects of smartphone application-based cognitive training at home on cognition in community-dwelling non-demented elderly individuals: A randomized controlled trial.

INTRODUCTION: We investigated whether cognitive function improves in elderly individuals after Application-based Cognitive Training at Home (ACTH) for 12 months. METHODS: A total of 389 non-demented elderly volunteers aged over 60 years were recruited and randomly assigned to the intervention or control group. The intervention group underwent daily ACTH (with regular feedback from the administrator) and monthly offline cognitive training in groups for 12 months. All participants received a computerized cognitive test battery called Inbrain Cognitive Screening Test (Inbrain-CST) at baseline and 6 and 12 months. The primary outcome was the change in the total composite score of Inbrain-CST, and secondary outcomes included changes in composite scores in five cognitive domains of Inbrain-CST. RESULTS: The intervention group outperformed the control group in terms of the total score (P = .001) and subscores of language (P < .001) and memory (P < .001) domains at 12 months. DISCUSSION: ACTH improved global cognition in community-dwelling non-demented elderly individuals.

A Validation Study of the Inbrain CST: a Tablet Computer-based Cognitive Screening Test for Elderly People with Cognitive Impairment.

BACKGROUND: Computerized versions of cognitive screening test could have advantages over pencil-and-paper versions by eliminating rater-dependent factors and saving the time required to score the tests and report the results. We developed a computerized cognitive screening test (Inbrain Cognitive Screening Test [Inbrain CST]) that takes about 30 minutes to administer on a touchscreen computer and is composed of neuropsychological tests already shown to be sensitive in detecting early cognitive decline in Alzheimer's disease (AD). The aims of this study were to 1) introduce normative data for Inbrain CST, 2) verify its reliability and validity, 3) assess clinical usefulness, and 4) identify neuroanatomical correlates of Inbrain CST. METHODS: The Inbrain CST runs on the Microsoft Windows 10 operating system and comprises 7 subtests that encompass 5 cognitive domains: attention, language, visuospatial, memory, and executive functions. First, we recruited 480 cognitively normal elderly people (age 50-90) from communities nationwide to establish normative data for Inbrain CST. Second, we enrolled 97 patients from our dementia clinic (26 with subjective cognitive decline [SCD], 42 with amnestic mild cognitive impairment [aMCI], and 29 with dementia due to AD) and investigated sensitivity and specificity of Inbrain CST for discriminating cognitively impaired patients from those with SCD using receiver operating characteristic (ROC) curve analyses. Third, we compared the Inbrain CST scores with those from another neuropsychological test battery to obtain concurrent validity and assessed test-retest reliability. Finally, magnetic resonance imaging (MRI)-based cortical thickness analyses were performed to provide anatomical substrates for performances on the Inbrain CST. RESULTS: First, in the normative sample, the total score on the Inbrain CST was significantly affected by age, years of education, and gender. Second, Inbrain CST scores among the three patient groups decreased in the order of SCD, aMCI, and AD dementia, and the ROC curve analysis revealed that Inbrain CST had good discriminative power for differentiating cognitively impaired patients from those with SCD. Third, the Inbrain CST subtests had high concurrent validity and test-retest reliability. Finally, in the cortical thickness analysis, each cognitive domain score and the total score of Inbrain CST showed distinct patterns of anatomical correlates that fit into the previously known brain-behavior relationship. CONCLUSION: Inbrain CST had good validity, reliability, and clinical usefulness in detecting cognitive impairment in the elderly. Furthermore, it showed neuroanatomical validity through MRI cortical thinning patterns. These results suggest that Inbrain CST is a useful cognitive screening tool with efficiency and validity to detect mild impairments in cognition in clinical settings.

The preclinical amyloid sensitive composite to determine subtle cognitive differences in preclinical Alzheimer's disease.

Recently, the focus of Alzheimer's disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aß+) and negative (Aß-) status in cognitively normal (CN) participants. A total of 423 CN participants with Aß positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aß+ and Aß- groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aß+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aß+ and Aß- was adequate (AUC = 0.764; 95% CI = 0.667-0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

A Comprehensive Evaluation of the Process of Copying a Complex Figure in Early- and Late-Onset Alzheimer Disease: A Quantitative Analysis of Digital Pen Data.

BACKGROUND: The Rey-Osterrieth Complex Figure Test (RCFT) is a neuropsychological test that is widely used to assess visual memory and visuoconstructional deficits in patients with cognitive impairment, including Alzheimer disease (AD). Patients with AD have an increased tendency for exhibiting extraordinary behaviors in the RCFT for selecting the drawing area, organizing the figure, and deciding the order of images, among other activities. However, the conventional scoring system based on pen and paper has a limited ability to reflect these detailed behaviors. OBJECTIVE: This study aims to establish a scoring system that addresses not only the spatial arrangement of the finished drawing but also the drawing process of patients with AD by using digital pen data. METHODS: A digital pen and tablet were used to copy complex figures. The stroke patterns and kinetics of normal controls (NCs) and patients with early-onset AD (EOAD) and late-onset AD (LOAD) were analyzed by comparing the pen tip trajectory, spatial arrangement, and similarity of the finished drawings. RESULTS: Patients with AD copied the figure in a more fragmented way with a longer pause than NCs (EOAD: P=.045; LOAD: P=.01). Patients with AD showed an increased tendency to draw the figures closer toward the target image in comparison with the NCs (EOAD: P=.005; LOAD: P=.01) Patients with AD showed the lower accuracy than NCs (EOAD: P=.004; LOAD: P=.002). Patients with EOAD and LOAD showed similar but slightly different drawing behaviors, especially in space use and in the initial stage of drawing. CONCLUSIONS: The digitalized complex figure test evaluated copying performance quantitatively and further elucidated the patients' ongoing process during copying. We believe that this novel approach can be used as a digital biomarker of AD. In addition, the repeatability of the test will delineate the process of executive functions and constructional organization abilities with disease progression.

The Cortical Neuroanatomy Related to Specific Neuropsychological Deficits in Alzheimer's Continuum.

BACKGROUND AND PURPOSE: In Alzheimer's continuum (a comprehensive of preclinical Alzheimer's disease [AD], mild cognitive impairment [MCI] due to AD, and AD dementia), cognitive dysfunctions are often related to cortical atrophy in specific brain regions. The purpose of this study was to investigate the association between anatomical pattern of cortical atrophy and specific neuropsychological deficits. METHODS: A total of 249 participants with Alzheimer's continuum (125 AD dementia, 103 MCI due to AD, and 21 preclinical AD) who were confirmed to be positive for amyloid deposits were collected from the memory disorder clinic in the department of neurology at Samsung Medical Center in Korea between September 2013 and March 2018. To analyze neuropsychological test-specific neural correlates representing the relationship between cortical atrophy measured by cortical thickness and performance in specific neuropsychological tests, a linear regression analysis was performed. Two neural correlates acquired by 2 different standardized scores in neuropsychological tests were also compared. RESULTS: Cortical atrophy in several specific brain regions was associated with most neuropsychological deficits, including digit span backward, naming, drawing-copying, verbal and visual recall, semantic fluency, phonemic fluency, and response inhibition. There were a few differences between 2 neural correlates obtained by different z-scores. CONCLUSIONS: The poor performance of most neuropsychological tests is closely related to cortical thinning in specific brain areas in Alzheimer's continuum. Therefore, the brain atrophy pattern in patients with Alzheimer's continuum can be predict by an accurate analysis of neuropsychological tests in clinical practice.

Clinical Effects of Frontal Behavioral Impairment: Cortical Thickness and Cognitive Decline in Individuals with Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment.

BACKGROUND: Frontal behavioral impairment (FrBI) is commonly observed in various degenerative diseases and refers to various behavioral symptoms. OBJECTIVE: We investigated the effects of the presence of FrBI on cortical thickness, and the longitudinal neuropsychological changes in people in the predementia stage. METHODS: A total of 794 individuals completed neuropsychological tests and the Frontal Behavioral Inventory (FBI) Questionnaire, and underwent magnetic resonance (MR) scanning. Participants were analyzed and grouped into non-FrBI (FBI = 0) or FrBI (FBI≥1). Cortical thickness was measured on MR images using a surface-based method. RESULTS: In total, 281 people with subjective cognitive decline (SCD) and 513 with amnestic mild cognitive impairment (aMCI) were assessed for FrBI. Relative to people without FrBI, those with FrBI presented reduced cortical thickness in the frontal, anterior temporal and lateral parietal regions (p < 0.05, FDR corrected). People with FrBI developed Alzheimer's disease, rather than behavioral variant frontotemporal dementia, as observed over seven years. Mixed effects models reported that people with FrBI have greater cognitive decline than those with non-FrBI in multiple domains, including language, memory, and executive functions (p < 0.05, FDR corrected). Furthermore, while negative FrBI symptoms (e.g., deficit behaviors) were associated with greater declines in multiple domains, positive FrBI symptoms (e.g., disinhibition symptoms) were related to declines in visuospatial function and verbal memory. Finally, the occurrence of both types of symptoms correlated with multi-domain cognitive decline. CONCLUSIONS: FrBI predicted worse clinical outcomes, including reduced cortical thickness and cognitive decline, which are not necessarily specific to frontal dysfunction.

A Nomogram for Predicting Amyloid PET Positivity in Amnestic Mild Cognitive Impairment.

BACKGROUND: Most clinical trials focus on amyloid-ß positive (Aß+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aß PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aß biomarker. OBJECTIVE: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aß+ aMCI and Aß-aMCI and to develop a clinically useful prediction model of Aß positivity on PET (PET-Aß+) in aMCI using a nomogram. METHODS: We recruited 523 aMCI patients who underwent Aß PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aß+ in aMCI patients was constructed using a logistic regression model. RESULTS: PET-Aß+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aß+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. CONCLUSIONS: The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aß+ in patients with aMCI.