Iron Oxide Nanoparticle-Incorporated Mesenchymal Stem Cells for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a neurodegenerative disease with multifactorial pathogenesis. However, most current therapeutic approaches for AD target a single pathophysiological mechanism, generally resulting in unsatisfactory therapeutic outcomes. Recently, mesenchymal stem cell (MSC) therapy, which targets multiple pathological mechanisms of AD, has been explored as a novel treatment. However, the low brain retention efficiency of administered MSCs limits their therapeutic efficacy. In addition, autologous MSCs from AD patients may have poor therapeutic abilities. Here, we overcome these limitations by developing iron oxide nanoparticle (IONP)-incorporated human Wharton's jelly-derived MSCs (MSC-IONPs). IONPs promote therapeutic molecule expression in MSCs. Following intracerebroventricular injection, MSC-IONPs showed a higher brain retention efficiency under magnetic guidance. This potentiates the therapeutic efficacy of MSCs in murine models of AD. Furthermore, human Wharton's jelly-derived allogeneic MSCs may exhibit higher therapeutic abilities than those of autologous MSCs in aged AD patients. This strategy may pave the way for developing MSC therapies for AD.

Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

Cilostazol Versus Aspirin on White Matter Changes in Cerebral Small Vessel Disease: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. METHODS: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. RESULTS: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02-0.89]). CONCLUSIONS: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01932203.

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.

Independent effects of amyloid and vascular markers on long-term functional outcomes: An 8-year longitudinal study of subcortical vascular cognitive impairment.

BACKGROUND AND PURPOSE: Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long-term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. METHODS: We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta-amyloid (Aß) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. RESULTS: During a 8.6-year follow-up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aß positivity (subdistribution hazard ratio [SHR] = 2.73), greater white matter hyperintensity (WMH) volume (SHR = 3.11) and ≥3 microbleeds (SHR = 2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio = 2.07) was an independent predictor of mortality. CONCLUSIONS: Our findings suggest that diverse imaging markers may predict long-term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long-term outcomes of SVCI.

IntraBrain Injector (IBI): A Stereotactic-Guided Device for Repeated Delivery of Therapeutic Agents Into the Brain Parenchyma.

BACKGROUND: To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. METHODS: We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. RESULTS: We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. CONCLUSION: Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.

Interaction between Alzheimer's Disease and Cerebral Small Vessel Disease: A Review Focused on Neuroimaging Markers.

Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) and tau, and subcortical vascular cognitive impairment (SVCI) is characterized by cerebral small vessel disease (CSVD). They are the most common causes of cognitive impairment in the elderly population. Concurrent CSVD burden is more commonly observed in AD-type dementia than in other neurodegenerative diseases. Recent developments in Aß and tau positron emission tomography (PET) have enabled the investigation of the relationship between AD biomarkers and CSVD in vivo. In this review, we focus on the interaction between AD and CSVD markers and the clinical effects of these two markers based on molecular imaging studies. First, we cover the frequency of AD imaging markers, including Aß and tau, in patients with SVCI. Second, we discuss the relationship between AD and CSVD markers and the potential distinct pathobiology of AD markers in SVCI compared to AD-type dementia. Next, we discuss the clinical effects of AD and CSVD markers in SVCI, and hemorrhagic markers in cerebral amyloid angiopathy. Finally, this review provides both the current challenges and future perspectives for SVCI.

Harmonisation of PET imaging features with different amyloid ligands using machine learning-based classifier.

PURPOSE: In this study, we used machine learning to develop a new method derived from a ligand-independent amyloid (Aß) positron emission tomography (PET) classifier to harmonise different Aß ligands. METHODS: We obtained 107 paired 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) PET images at the Samsung Medical Centre. To apply the method to FMM ligand, we transferred the previously developed FBB PET classifier to test similar features from the FMM PET images for application to FMM, which in turn developed a ligand-independent Aß PET classifier. We explored the concordance rates of our classifier in detecting cortical and striatal Aß positivity. We investigated the correlation of machine learning-based cortical tracer uptake (ML-CTU) values quantified by the classifier between FBB and FMM. RESULTS: This classifier achieved high classification accuracy (area under the curve = 0.958) even with different Aß PET ligands. In addition, the concordance rate of FBB and FMM using the classifier (87.5%) was good to excellent, which seemed to be higher than that in visual assessment (82.7%) and lower than that in standardised uptake value ratio cut-off categorisation (93.3%). FBB and FMM ML-CTU values were highly correlated with each other (R = 0.903). CONCLUSION: Our findings suggested that our novel classifier may harmonise FBB and FMM ligands in the clinical setting which in turn facilitate the biomarker-guided diagnosis and trials of anti-Aß treatment in the research field.

Honorific Speech Impairment: A Characteristic Sign of Frontotemporal Dementia.

BACKGROUND: Individuals with the behavioral variant of frontotemporal dementia (bvFTD) exhibit various levels of abulia, disinhibition, impaired judgment, and decline in executive function. Empirical evidence has shown that individuals with bvFTD also often exhibit difficulty using honorific speech, which expresses respect to another party or addressee. OBJECTIVE: To analyze differences in the ability to use honorific speech among individuals with bvFTD, individuals with dementia of the Alzheimer type (AD dementia), and individuals with normal cognition (NC). METHOD: A total of 53 native Korean speakers (13 bvFTD, 20 AD dementia, and 20 NC) completed an experimental honorific speech task (HST) that involved both expressive and receptive tasks. We analyzed the number of correct responses and error patterns separately for an expressive task and for a receptive task. RESULTS: The bvFTD group had significantly fewer correct responses on the HST compared with the AD dementia and NC groups. The bvFTD group exhibited more misjudgment errors in identifying nonhonorific speech as honorific speech in the expressive task, and significantly longer response times in the receptive task, than the AD dementia and NC groups. Significant associations were identified between HST scores and cortical atrophy in the temporal and frontotemporal lobes. CONCLUSION: A decline in the ability to use honorific speech may be a diagnosable behavioral and psychiatric symptom for bvFTD in Korean-speaking individuals. This decline in individuals with bvFTD could be attributed to multiple factors, including social manners (politeness) and impaired social language use ability (pragmatics).

Distributed Patterns of Functional Connectivity Predict Working Memory Performance in Novel Healthy and Memory-impaired Individuals.

Individual differences in working memory relate to performance differences in general cognitive ability. The neural bases of such individual differences, however, remain poorly understood. Here, using a data-driven technique known as connectome-based predictive modeling, we built models to predict individual working memory performance from whole-brain functional connectivity patterns. Using n-back or rest data from the Human Connectome Project, connectome-based predictive models significantly predicted novel individuals' 2-back accuracy. Model predictions also correlated with measures of fluid intelligence and, with less strength, sustained attention. Separate fluid intelligence models predicted working memory score, as did sustained attention models, again with less strength. Anatomical feature analysis revealed significant overlap between working memory and fluid intelligence models, particularly in utilization of prefrontal and parietal regions, and less overlap in predictive features between working memory and sustained attention models. Furthermore, showing the generality of these models, the working memory model developed from Human Connectome Project data generalized to predict memory in an independent data set of 157 older adults (mean age = 69 years; 48 healthy, 54 amnestic mild cognitive impairment, 55 Alzheimer disease). The present results demonstrate that distributed functional connectivity patterns predict individual variation in working memory capability across the adult life span, correlating with constructs including fluid intelligence and sustained attention.

Strictly Lobar Microbleeds Reflect Amyloid Angiopathy Regardless of Cerebral and Cerebellar Compartments.

BACKGROUND AND PURPOSE: We aimed to determine whether lobar cerebellar microbleeds or concomitant lobar cerebellar and deep microbleeds, in the presence of lobar cerebral microbleeds, attribute to underlying advanced cerebral amyloid angiopathy pathology or hypertensive arteriopathy. METHODS: We categorized 71 patients with suspected cerebral amyloid angiopathy markers (regardless of the presence of deep and cerebellar microbleeds) into 4 groups according to microbleed distribution: L (strictly lobar cerebral, n=33), L/LCbll (strictly lobar cerebral and strictly lobar cerebellar microbleeds, n=13), L/Cbll/D (lobar, cerebellar, and deep microbleeds, n=17), and L/D (lobar and deep, n=8). We additionally categorized patients with cerebellar microbleeds into 2 groups according to dentate nucleus involvement: strictly lobar cerebellar (n=16) and dentate (n=14). We then compared clinical characteristics, Aß (amyloid-ß) positivity on PET (positron emission tomography), magnetic resonance imaging cerebral amyloid angiopathy markers, and cerebral small vessel disease burden among groups. RESULTS: The frequency of Aß positivity was higher in the L and L/LCbll groups (81.8% and 84.6%) than in the L/Cbll/D and L/D groups (37.5% and 29.4%; P<0.001), while lacune numbers were lower in the L and L/LCbll groups (1.7±3.3 and 1.7±2.6) than in the L/Cbll/D and L/D groups (8.0±10.3 and 13.4±17.7, P=0.001). The L/LCbll group had more lobar cerebral microbleeds than the L group (93.2±121.8 versus 38.0±40.8, P=0.047). The lobar cerebellar group had a higher Aß positivity (75% versus 28.6%, P=0.011) and lower lacune number (2.3±3.7 versus 8.6±1.2, P=0.041) than the dentate group. CONCLUSIONS: Strictly lobar cerebral and cerebellar microbleeds are related to cerebral amyloid angiopathy, whereas any combination of concurrent lobar and deep microbleeds suggest hypertensive angiopathy regardless of cerebral or cerebellar compartments.

Correction to: Staging and quantification of florbetaben PET images using machine learning: impact of predicted regional cortical tracer uptake and amyloid stage on clinical outcomes.

Incorrect acknowledgments.

Staging and quantification of florbetaben PET images using machine learning: impact of predicted regional cortical tracer uptake and amyloid stage on clinical outcomes.

PURPOSE: We developed a machine learning-based classifier for in vivo amyloid positron emission tomography (PET) staging, quantified cortical uptake of the PET tracer by using a machine learning method, and investigated the impact of these amyloid PET parameters on clinical and structural outcomes. METHODS: A total of 337 18F-florbetaben PET scans obtained at Samsung Medical Center were assessed. We defined a feature vector representing the change in PET tracer uptake from grey to white matter. Using support vector machine (SVM) regression and SVM classification, we quantified the cortical uptake as predicted regional cortical tracer uptake (pRCTU) and categorised the scans as positive and negative. Positive scans were further classified into two stages according to the striatal uptake. We compared outcome parameters among stages and further assessed the association between the pRCTU and outcome variables. Finally, we performed path analysis to determine mediation effects between PET variables. RESULTS: The classification accuracy was 97.3% for cortical amyloid positivity and 91.1% for striatal positivity. The left frontal and precuneus/posterior cingulate regions, as well as the anterior portion of the striatum, were important in determination of stages. The clinical scores and magnetic resonance imaging parameters showed negative associations with PET stage. However, except for the hippocampal volume, most outcomes were associated with the stage through the complete mediation effect of pRCTU. CONCLUSION: Using a machine learning algorithm, we achieved high accuracy for in vivo amyloid PET staging. The in vivo amyloid stage was associated with cognitive function and cerebral atrophy mostly through the mediation effect of cortical amyloid.

Correction to: Staging and quantification of florbetaben PET images using machine learning: impact of predicted regional cortical tracer uptake and amyloid stage on clinical outcomes.

The Table 2 in the original version of this article contained a mistake in the alignment. Correct Table 2 presentation is presented here.

Correction to: A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

Funding information from the original version of this article was incomplete. Complete information is presented here.

A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

PURPOSE: We developed a new method to directly calculate Centiloid (CL) units of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) without conversion to the PiB standardized uptake value ratio (SUVR). METHODS: Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method. RESULTS: Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R2 = 0.97, FMM dcCL = 0.97 × FBB dcCL + 1.64) and the standard method (R2 = 0.97, FMM CLstandard = 0.79 × FBB CLstandard + 1.36). However, the CL variations between FBB and FMM were smaller when calculated by dcCL method (6.15) than when calculated by the previous method (10.22; P = 0.01). CONCLUSIONS: Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Application of an amyloid and tau classification system in subcortical vascular cognitive impairment patients.

OBJECTIVE: To apply an AT (Aß/tau) classification system to subcortical vascular cognitive impairment (SVCI) patients following recently developed biomarker-based criteria of Alzheimer's disease (AD), and to investigate its clinical significance. METHODS: We recruited 60 SVCI patients who underwent the neuropsychological tests, brain MRI, and 18F-florbetaben and 18F-AV1451 PET at baseline. As a control group, we further recruited 27 patients with AD cognitive impairment (ADCI; eight Aß PET-positive AD dementia and 19 amnestic mild cognitive impairment). ADCI and SVCI patients were classified as having normal or abnormal Aß (A-/A+) and tau (T-/T+) based on PET results. Across the three SVCI groups (A-, A+T-, and A+T+SVCI), we compared longitudinal changes in cognition, hippocampal volume (HV), and cortical thickness using linear mixed models. RESULTS: Among SVCI patients, 33 (55%), 20 (33.3%), and seven (11.7%) patients were A-, A+T-, and A+T+, respectively. The frequency of T+ was lower in A+SVCI (7/27, 25.9%) than in A+ADCI (14/20, 70.0%, p = 0.003) which suggested that cerebral small vessel disease affected cognitive impairments independently of A+. A+T-SVCI had steeper cognitive decline than A-SVCI. A+T+SVCI also showed steeper cognitive decline than A+T-SVCI. Also, A+T-SVCI had steeper decrease in HV than A-SVCI, while cortical thinning did not differ between the two groups. A+T+SVCI had greater global cortical thinning compared with A+T-SVCI, while declines in HV did not differ between the two groups. CONCLUSION: This study showed that the AT system successfully characterized SVCI patients, suggesting that the AT system may be usefully applied in a research framework for clinically diagnosed SVCI.

Functional connectivity associated with tau levels in ageing, Alzheimer's, and small vessel disease.

In Alzheimer's disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout the cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological tau have been observed in normal ageing and small vessel disease, suggesting a spatially ordered distribution of tau pathology across normal ageing and different diseases. In vitro findings suggest that pathological tau may spread 'prion-like' across neuronal connections in an activity-dependent manner. Supporting this notion, functional brain networks show a spatial correspondence to tau deposition patterns. However, it remains unclear whether higher network-connectivity facilitates tau propagation. To address this, we included 55 normal aged elderly (i.e. cognitively normal, amyloid-negative), 50 Alzheimer's disease patients (i.e. amyloid-positive) covering the preclinical to dementia spectrum, as well as 36 patients with pure (i.e. amyloid-negative) vascular cognitive impairment due to small vessel disease. All subjects were assessed with AV1451 tau-PET and resting-state functional MRI. Within each group, we computed atlas-based resting-state functional MRI functional connectivity across 400 regions of interest covering the entire neocortex. Using the same atlas, we also assessed within each group the covariance of tau-PET levels among the 400 regions of interest. We found that higher resting-state functional MRI assessed functional connectivity between any given region of interest pair was associated with higher covariance in tau-PET binding in corresponding regions of interest. This result was consistently found in normal ageing, Alzheimer's disease and vascular cognitive impairment. In particular, inferior temporal tau-hotspots, as defined by highest tau-PET uptake, showed high predictive value of tau-PET levels in functionally closely connected regions of interest. These associations between functional connectivity and tau-PET uptake were detected regardless of presence of dementia symptoms (mild cognitive impairment or dementia), amyloid deposition (as assessed by amyloid-PET) or small vessel disease. Our findings suggest that higher functional connectivity between brain regions is associated with shared tau-levels, supporting the view of prion-like tau spreading facilitated by neural activity.

The Dementias Platform UK (DPUK) Data Portal.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

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.