Subtle Cognitive Changes Research Articles

Using Digital Tools to Advance Alzheimer\u2019s Drug Trials During a Pandemic: The EU/US CTAD Task Force

The 2020 COVID-19 pandemic has disrupted Alzheimer’s disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer’s Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Current advances in digital cognitive assessment for preclinical Alzheimer's disease.

There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer's disease (AD) rapidly, cost‐effectively, and with high sensitivity. Concurrently, the landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech‐adoption increases, and external events (i.e., COVID‐19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in‐clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study‐provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD.

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages.

Spinocerebellar ataxias type 2 (SCA2) is an autosomal dominant inherited disease caused by expanded trinucleotide repeats (≥32 CAG) within the coding region of ATXN2 gene. Age of disease onset primarily depends on the length of the expanded region. The majority of subjects carrying the mutation remain free of clinical signs for few decades (“pre-symptomatic” stage), but in proximity of disease onset subtle neurophysiological, cognitive, and structural brain imaging changes may occur. Aims of the present study are to determine the time-window in which early clinical and neurodegenerative MRI changes may be identified, and to evaluate the rate of the disease progression in both preclinical and early disease phases. We performed a 1-year longitudinal study in 42 subjects: 14 SCA2 patients (mean age 39 years, disease duration 7 years, SARA score 9 points), 13 presymptomatic SCA2 subjects (preSCA2, mean age 39 years, expected time to disease onset 16 years), and 15 gene-negative healthy controls (mean age 33 years). All participants underwent genetic test, neurological examination, cognitive tests, and brain MRI. Evaluations were repeated at 1-year interval. Baseline MRI evaluations in SCA2 patients showed significant atrophy in cerebellum, brainstem, basal ganglia and cortex compared to controls, while preSCA2 subjects had isolated volume loss in the pons, and cortical thinning in specific frontal and parietal areas, namely rostral-middle-frontal and precuneus. One-year longitudinal follow-up demonstrated, in SCA2 patients, volume reduction in cerebellum, pons, superior cerebellar peduncles, and midbrain, and only in the cerebellum in preSCA2 subjects. No progression in clinical or cognitive measures was observed in preSCA2 subjects. The rate of volume loss in the cerebellum and subcortical regions greatly differed between patients and preSCA2. In conclusion, our pilot study demonstrated that MRI measures are highly sensitive to identify longitudinal structural changes in SCA2 patients, and in preSCA2 up to a decade before expected disease onset. These findings may contribute in the understanding of early neurodegenerative processes and may be useful in future therapeutical trials.

Cognitive profile of mild behavioral impairment (MBI) in brain health registry participants

AbstractBackgroundNon‐cognitive markers may be utilized in dementia risk assessments. Mild behavioural impairment (MBI) is a validated neurobehavioural syndrome developed by an Alzheimer’s Association‐ISTAART working group including the following criteria: 1) later life emergent and persistent neuropsychiatric symptoms; 2) representing a change from longstanding personality or patterns of behaviour; 3) not better accounted for by psychiatric conditions or life stressors. MBI as an at‐risk state for cognitive decline and dementia and may be the earliest manifestations of disease for some. We investigated whether MBI, measured with the MBI checklist, was associated with cognitive changes in older adults in the Brain Health Registry (BHR).MethodsWe analyzed data from 5225 participants in BHR. Participants were included if they completed Lumosity cognitive tests (memory span, reverse memory span, trailmaking, go‐no‐go) and an informant‐rated MBI‐C. We excluded participants with major neurological, psychiatric or developmental disorders. Using cutpoints to dichotomize MBI+ and MBI‐ participants (MBI‐C > 5, 6, 7), univariate ANOVA was used to determine whether people with MBI also showed impairment in cognitive test performance. ANOVAs covaried for age, sex, education, and time between test administration and MBI‐C completion. All assessments were completed remotely, using the BHR online registry.ResultsThe final sample included 802 participants with a mean age of 66.97(SD 10.71), of which 515/802 were females (64.21%). The number and percent of MBI‐C+ participants was 62 (7.7%), 53 (6.6%), and 48 (6.0%) at cutpoints of MBI‐C >5, >6, and >7 respectively. MBI+ participants had significantly poorer memory span, poorer reverse memory span, longer trail‐making completion time, and more trail‐making errors (see Table 1 for statistical reporting). A significantly greater number of men were classified as MBI+ at all 3 cutpoints (p< 0.001).ConclusionsIn a large cohort of older adults in BHR, MBI assessed remotely and unsupervised using an online interface, was associated with poorer cognition in the domains of memory and executive function compared to those without MBI. Utilizing the MBI‐C in case finding may be a simple, efficient, and scalable way to detect individuals with subtle cognitive changes, for further assessment and workup, or potential inclusion in clinical trials.

Performance and intrusion errors on challenging cognitive assessments associate with subjective cognitive decline

AbstractBackgroundSubjective cognitive decline (SCD) in ostensibly cognitively normal older adults has been proposed to reflect preclinical Alzheimer’s disease (AD). Yet traditional neuropsychological tests have inconsistently linked SCD and cognitive performance, possibly reflecting the lack of sensitivity and specificity in such tests to capture subtle cognitive changes. Indeed, novel cognitive tests as well as intrusion errors appear to be more closely associated with preclinical AD biomarkers. However, there is limited investigation into the association of SCD with these cognitive outcomes. This study examines SCD in relation to the main outcomes and intrusion errors on two novel challenging cognitive tasks, and a traditional neuropsychological test.Method94 healthy older adults with a mean age of 73 years (SD=7.36), and education of 17 years (SD=2.34) were recruited for this study. Participants completed three SCD questionnaires regarding common cognitive difficulties in memory, language, attention and executive functioning. A single factor score was derived as main outcome for SCD. Cognitive assessment included the Loewenstein‐Acevedo Scale for Semantic Interference and Learning (LASSI‐L), the Face‐Name Associative Memory Exam (FNAME) task, and the Selective Reminding Test (SRT). Main outcomes for each measure included: SRT (total and delayed recall and intrusion errors); LASSI‐L (recovery from semantic interference, percentage of intrusions errors, total semantically related intrusions (SRI) and competing item intrusions (CII)); FNAME (total names recalled, SRI and CII). Demographically adjusted linear regressions were conducted to examine the unique contribution of performance and intrusion errors on each measure to SCD.ResultBoth FNAME names recall (β=‐.24, p=.027) and SRI (β=.25, p=.015) were independently associated with SCD, while overall intrusions and CII were not (p>.05). The LASSI‐L overall intrusions (β=‐ .30, p=.009) and CII (β=‐ .29, p=.014) were also associated with SCD, while SRI and recovery from semantic interference were not. (p>.05). No SRT outcomes were associated with SCD (p>.05)ConclusionSCD appears to capture subtle changes on sensitive cognitive measures proposed to be indicative of preclinical AD. Results support the use of both main outcomes and intrusion errors on these cognitive tests, as they may each reveal sensitive information regarding various mechanisms that can breakdown in early AD.

Reduced awareness of cognitive decline is associated with brain amyloid load in asymptomatic elderly individuals at risk for AD: A longitudinal study

AbstractBackgroundIt has recently been proposed that the awareness of cognitive decline (ACD) may already be slightly reduced in the preclinical phase of AD, in the presence of subtle cognitive changes. This is a recent field of research, and the few studies available do not allow to appreciate the actual evolution of ACD in the pre‐dementia phases of AD. The present study describes the longitudinal trajectory of an index of ACD (ACDI) over 3 years in a cohort of cognitively‐normal elderly, its association to AD biomarkers, as well as its impact on cognitive scores’ evolution.Method314 elderly memory complainers, as just as many study‐partners, were followed‐up for 3 years. Brain glucose metabolism and amyloid load were assessed at baseline; screening cognitive tests were performed every 6 months, and a comprehensive neuropsychological evaluation every 12 months. The ACDI was based on the subject‐informant discrepancy on a questionnaire evaluating the subject’s cognitive decline. We performed a Latent Class Linear Mixed Model (LCLMM) to identify different trends of evolution of the ACDI over time, and Generalized Linear Mixed Models to analyse the impact of the baseline ACDI on the evolution of cognitive scores.ResultThe LCLMM identified three classes of subjects sharing similar longitudinal trajectories of the ACDI. Most subjects (76.8%) have accurate ACD (Class 2), and have been considered as the reference group. 18.95% of subjects showed heightened ACD (“worried‐well” individuals). They were comparable to subjects with accurate ACD in terms of AD biomarkers. 4.25% of the sample showing low ACD had higher amyloid burden than the reference group, and were mostly men. The GLMM found no overall effect of baseline ACDI on the evolution of the cognitive scores.ConclusionThe study of ACD in AD, its evolution and correlates is a topic of growing interest, as it is, notably, a piece of the larger understanding of the pre‐dementia phases of AD. This can be useful for a timely diagnosis of AD, and for the selection of populations to be included in clinical trials.

Classifying multiple sclerosis patients on the basis of SDMT performance using machine learning

Objective: To build a model to predict cognitive status reflecting structural, functional, and white matter integrity changes in early multiple sclerosis (MS). Methods: Based on Symbol Digit Modalities Test (SDMT) performance, 183 early MS patients were assigned “lower” or “higher” performance groups. Three-dimensional (3D)-T2, T1, diffusion weighted, and resting-state magnetic resonance imaging (MRI) data were acquired in 3T. Using Random Forest, five models were trained to classify patients into two groups based on 1—demographic/clinical, 2—lesion volume/location, 3—local/global tissue volume, 4—local/global diffusion tensor imaging, and 5—whole-brain resting-state-functional-connectivity measures. In a final model, all important features from previous models were concatenated. Area under the receiver operating characteristic curve (AUC) values were calculated to evaluate classifier performance. Results: The highest AUC value (0.90) was achieved by concatenating all important features from neuroimaging models. The top 10 contributing variables included volumes of bilateral nucleus accumbens and right thalamus, mean diffusivity of left cingulum-angular bundle, and functional connectivity among hubs of seven large-scale networks. Conclusion: These results provide an indication of a non-random brain pattern mostly compromising areas involved in attentional processes specific to patients who perform worse in SDMT. High accuracy of the final model supports this pattern as a potential neuroimaging biomarker of subtle cognitive changes in early MS.

Failure to stop autocorrect errors in reading aloud increases in aging especially with a positive biomarker for Alzheimer's disease.

The present study examined the effects of aging and CSF biomarkers of Alzheimer's disease (AD) on the ability to control production of unexpected words in connected speech elicited by reading aloud. Fifty-two cognitively healthy participants aged 66-86 read aloud 6 paragraphs with 10 malapropisms including 5 on content words (e.g., "window cartons" that elicited autocorrect errors to "window curtains") and 5 on function words (e.g., "thus concept" that elicited autocorrections to "this concept") and completed a battery of neuropsychological tests including a standardized Stroop task. Reading aloud elicited more autocorrect errors on function than content words, but these were equally correlated with age and Aβ1-42 levels. The ability to stop autocorrect errors declined in aging and with lower (more AD-like) levels of Aβ1-42, and multiplicatively so, such that autocorrect errors were highest in the oldest-old with the lowest Aβ1-42 levels. Critically, aging effects were significant even when controlling statistically for Aβ1-42. Finally, both autocorrect and Stroop errors were correlated with Aβ1-42, but only autocorrect errors captured unique variance in predicting Aβ1-42 levels. Reading aloud requires simultaneous planning and monitoring of upcoming speech. These results suggest that healthy aging leads to decline in the ability to intermittently monitor for and detect conflict during speech planning and that subtle cognitive changes in preclinical AD magnify this aging deficit. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evaluation of Naturalistic Driving Behavior Using In-Vehicle Monitoring Technology in Preclinical and Early Alzheimer's Disease.

Cognitive impairment is a significant risk factor for hazardous driving among older drivers with Alzheimer’s dementia, but little is known about how the driving behavior of mildly symptomatic compares with those in the preclinical, asymptomatic phase of Alzheimer’s disease (AD). This study utilized two in-car technologies to characterize driving behavior in symptomatic and preclinical AD. The goals of this pilot study were to (1) describe unsafe driving behaviors in individuals with symptomatic early AD using G-force triggered video capture and (2) compare the driving habits of these symptomatic AD drivers to two groups of cognitively normal drivers, those with and those without evidence of cerebral amyloidosis (CN/A+ and CN/A−) using a global positioning system (GPS) datalogger. Thirty-three drivers (aged 60+ years) were studied over 3 months. G-force triggered video events captured instances of near-misses/collisions, traffic violations, risky driver conduct, and driving fundamentals. GPS data were sampled every 30 s and all instances of speeding, hard braking, and sudden acceleration were recorded. For the early AD participants, video capture identified driving unbelted, late response, driving too fast for conditions, traffic violations, poor judgment, and not scanning intersections as the most frequently occurring safety errors. When evaluating driving using the GPS datalogger, hard breaking events occurred most frequently on a per trip basis across all three groups. The CN/A+ group had the lowest event rate across all three event types with lower instances of speeding. Slower psychomotor speed (Trail Making Part A) was associated with fewer speeding events, more hard acceleration events, and more overall events. GPS tracked instances of speeding were correlated with total number of video-captured near-collisions/collisions and driving fundamentals. Results demonstrate the utility of electronic monitoring to identify potentially unsafe driving events in symptomatic and preclinical AD. Results suggest that drivers with preclinical AD may compensate for early, subtle cognitive changes by driving more slowly and cautiously than healthy older drivers or those with cognitive impairment. Self-regulatory changes in driving behavior appear to occur in the preclinical phase of AD, but safety concerns may not arise until symptoms of cognitive impairment emerge and the ability to self-monitor declines.

Effect of short-term memory and working memory in diabetes with comorbidities condition

Cognitive function refers to the ability of humans to function normally which includes physical as well as mental interpretation like ability to focus, concentrate, learn, plan, determine, execute, manipulate and problem solving. Etiologic of cognitive dysfunction includes AD, depression, anxiety and vascular dementia, hippocampal sclerosis etc., Diabetes associated with cognitive decline are related to short fall of learning and memory. Cognitive impairment/dysfunction in diabetic patients has been divided into three stages, stage one, stage two and stage three. Stage one, occur in all groups of different ages and it is characterized by mild and subtle changes in cognition. Deficit in short-term memory and working memory leads to major problems like Alzheimer disease and dementia. The pathophysiology of cognitive decline associated involves microvascular injury, hyperglycaemia, insulin resistance and oxidative stress. Diabetes associated with comorbidities condition leads to decrease in short-term memory and working memory. From this review we observed short term memory retains small amount of data in cognizance which are readily available state for short period of time whereas working memory manipulates the information through visual and auditory storage and it is important in understanding and improving the memory. Conclusion of this review is that, there is a decrease in short-term memory and working memory in type 2 diabetes patient condition. But there is no evidence of which type comorbidity condition affects more in short-term memory and working memory. So, further research study to be carried out.

Prevalence of mild cognitive problems in Flemish Nursing homes

Abstract Background Mild cognitive decline in Nursing Home (NH) residents without dementia is often noted very late since cognitive demands are relatively low in this setting. Therefore, subtle cognitive changes could remain undetected. This study aimed to evaluate the prevalence of mild cognitive problems in NHs. Methods First, a file study was performed to exclude residents with a diagnosis of dementia or known cognitive problems (Mini Mental State Examination-MMSE < 24) in 16 NHs. Second, remaining residents were screened for cognition with the Montreal Cognitive Assessment (MoCA). Also, an evaluation of functionality (ADL-Questionnaire), mood (Geriatric Depression Scale), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire) and subjective memory complaints (Informant Questionnaire on Cognitive Decline) was performed. Results On a total of 1339 residents, 229 persons (17.1%) had no diagnosis of dementia and an MMSE >23. Based on MoCA-cut-offs 2.7% (n = 36), 11.4% (n = 152) and 3.1% (n = 41) could be labelled as cognitively normal (>25), mild cognitive impairment (>16 and <26) and mild dementia (<17) respectively. This resulted in a prevalence of undetected mild cognitive problems of 14.5% (n = 193) in the total NH population. Significant differences between the 3 groups were found for functionality, mood, neuropsychiatric symptoms and subjective memory complaints (all p < 0.05). Conclusions Considering their advanced age NH residents are vulnerable to develop dementia. This study showed that an important part of them has unnoticed mild cognitive problems. NHs should be aware of this risk group in order to provide adequate prevention and support.

Sleep disorders and risk of dementia in patients with new-onset type 2 diabetes: A nationwide population-based cohort study.

This study examined the relationship between sleep disorders and the risk of dementia in patients with newly diagnosed type 2 diabetes. This study used the Korean Health Screening Cohort data and included 39 135 subjects aged ≥40 years with new-onset type 2 diabetes between 2004 and 2007, with follow-up throughout 2013. Sleep disorders were measured by F51(sleep disorders not due to a substance or known physiological condition) or G47(sleep disorders) under International Classification of Diseases, Tenth Revision (ICD-10) codes as a primary diagnosis, and the adjusted hazard ratio (AHR) and 95% CI of all-cause dementia, Alzheimer disease, vascular dementia, and other dementia were estimated using multivariable Cox proportional hazards regression models. In the patients with type 2 diabetes with an age range between 42 and 84 years (M = 57.8, SD = 9.5), this study identified 2059 events of dementia during an average follow-up time of 5.7 years. In patients with type 2 diabetes, subjects with sleep disorders were associated with an increased risk of all-cause dementia (AHR, 1.46; 95% CI, 1.19-1.80), Alzheimer disease (AHR, 1.39; 95% CI, 1.02-1.88), and other dementia (AHR, 1.69; 95% CI, 1.23-2.31) compared to those without sleep disorders. Men (AHR, 1.93; 95% CI, 1.42-2.62) and older adults (AHR, 1.70; 95% CI, 1.35-2.15) with sleep disorders were associated with an increased risk of dementia than their counterparts without sleep disorders among patients with type 2 diabetes. These findings suggest that sleep disorders are significantly associated with an increased risk of dementia in patients with new-onset type 2 diabetes.

Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease

Due to advances in the early detection of Alzheimer's disease (AD) biomarkers including beta-amyloid (Aβ), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with mild cognitive impairment (MCI) and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of Aβ and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale-Revised. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with “preclinical AD,” or cognitively unimpaired adults with positive Aβ deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B (PiB). We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP). We performed binary logistic regression models with story recall score as predictor and Aβ status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with Aβ status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p = .01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with Aβ, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to Aβ deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.

Information Processing in Migraine: A Review of Studies on P300.

Subjective cognitive dysfunction is common among migraineurs. The aim of this review is to evaluate the usefulness of psychophysiology by means of the P300 component of the event-related potential in the understanding of subtle and sub-clinical changes in cognition that may occur during and between migraine episodes. Some P300 studies suggest a potential impairment of information processing, as reflected by only few findings of interictal decreased amplitude and prolonged latency, ictal augmented amplitude and prolonged latency, changes in cognitive habituation, and limited capacity to relocate attention away from painful stimuli. P300 may represent a valuable aid for clinicians to identify patients at risk of chronicization and cognitive weakening due to neurovascular complications; in this perspective a research agenda may be planned involving larger numbers of patients undergoing psychophysiological studies.

Study of Cognitive Evoked Potentials in Type 2 Diabetes Mellitus

Background: The completesyndrome of diabetes mellitus,related metabolic aberrations anddiabetic complications is posing a major threat in the 21st century. Cognitive dysfunction is a well known complication of diabetes which continues to be investigated. Aims and Objectives: To evaluate the cognitive functions using electrophysiological (P300 latencies) tests in diabetics and non diabetics in the age group of 40 - 59 years with same gender proportion, to analyze whether cognition is affected in diabetics when compared to non diabetics and to know the usefulness of electrophysiological (P300latencies) tests in detecting subtle cognitive changes. Materials and Method: The study was conducted on 50 diabetics and 50 non diabetics aged between 40 and 59 years. Cognition was assessed using P300 potential.The evoked potential data analysis was done using Student unpaired T test to compare the mean of two groups. Results: The absolute peak latencies of P3 component of endogenous cognitive evoked potentials was significantly prolonged among diabetics (334.8 + 20.8) as compared to controls (285.7 + 14.9). There was no statistically significant difference between groups when analyzed for N2 in Czand Fz. Conclusion: This study identifies prevalence of cognitive dysfunction in diabetic patients when assessed using electrophysiological tests.Good cognitive function is critical to safely manage diabetesand draws attention to various challenges in their management. Clinicians should consider screening for cognitive function in diabetics using P300, as it is effective in detecting subtle changes much before their clinical manifestation.

Identification of Pre-Clinical Alzheimer's Disease in a Population of Elderly Cognitively Normal Participants.

Alzheimer's disease (AD) has a long pathological process, with an approximate lead-time of 20 years. During the early stages of the disease process, little evidence of the building pathology is identifiable without cerebrospinal fluid and/or imaging analyses. Clinical manifestations of AD do not present until irreversible pathological changes have occurred. Given an opportunity to provide treatment prior to irreversible pathological change, this study aims to identify a subgroup of cognitively normal (CN) participants from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), where subtle changes in cognition are indicative of early AD-related pathology. Using a Bayesian method for unsupervised clustering via mixture models, we define an aggregate measure of posterior probabilities (AMPP score) establishing the likelihood of pre-clinical AD. From Baseline through to 54 months, visuo-spatial function had the greatest contribution to the AMPP score, followed by attention and processing speed and visual memory. Participants with the highest AMPP scores had both increasing neo-cortical amyloid burden and decreasing hippocampus volume over 54 months, compared to those in the lowest category with stable amyloid burden and hippocampus volume. The identification of a possible pre-clinical stage in CN participants via this method, without the aid of disease specific biomarkers, represents an important step in utilizing the strength of cognitive composite scores for the early detection of AD pathology.

Amyloid-β Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Amyloid-β Positivity

BackgroundStage 1 of the National Institute on Aging–Alzheimer’s Association’s proposed Alzheimer’s disease continuum is defined as amyloid-β (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests that subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ. MethodsWe examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite, Alzheimer’s Disease Neuroimaging Initiative (ADNI) memory factor composite) with progression to Aβ positivity in 292 nondemented, Aβ-negative ADNI participants. Additional analyses included continuous cerebrospinal fluid biomarker levels to examine the effects of subthreshold pathology. ResultsForty participants progressed to Aβ positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline cerebrospinal fluid phosphorylated tau and subthreshold Aβ were associated with increased odds of progression to Aβ positivity. Nevertheless, baseline ADNI memory factor composite performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (Preclinical Alzheimer Cognitive Composite was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline Preclinical Alzheimer Cognitive Composite still significantly predicted progression time to Aβ positivity (ADNI memory factor composite was trend level). ConclusionsThe possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low-cost, noninvasive cognitive measures can be informative for determining who is likely to progress to Aβ positivity, even after accounting for baseline subthreshold biomarker levels.

Effects of Home-Based Working Memory Training on Visuo-Spatial Working Memory in Parkinson's Disease: A Randomized Controlled Trial.

Background:Cognitive impairment is a very frequent and severe nonmotor symptom of Parkinson’s disease (PD). Early intervention in this at-risk group for cognitive decline may be crucial for long-term preservation of cognitive functions. Computerized working memory training (WMT) has been proven beneficial in non-PD patient populations, but such evidence is still needed for patients with PD.Objective:This study aimed to evaluate the effect of WMT on visuo-spatial working memory (WM) in cognitively unimpaired patients with PD.Methods:A single-blind randomized controlled trial encompassing 76 patients with PD but no cognitive impairment according to level II diagnostic criteria was conducted. Thirty-seven patients engaged in home-based adaptive WMT 5 times per week for a period of 5 weeks, whereas the remaining patients were in the waiting list arm of the study (control group [CG]). Working memory performance was evaluated using a computerized task before and after intervention and at 14-week follow-up, allowing to quantify the precision of WM on a continuous scale, ie, to test not only if an item was remembered but also how well the location of this item was retained.Results:Coincidently, the WMT group showed slightly worse WM performance compared with the CG at baseline, which was ameliorated after WMT. This training-induced effect remained stable until follow-up.Conclusion:Patients showing relatively low WM performance, despite not formally diagnosable as Parkinson’s disease with mild cognitive impairment (PD-MCI), seem to benefit from home-based WMT. Thus, WMT could potentially be implemented in future trials as a time- and cost-efficient route to counteract subtle cognitive changes in early disease stages.Trial registration:German Clinical Trial Register (drks.de, DRKS00009379)

Getting a Feel for Systems

In response to the challenges of teaching a course in environmental ethics to engineering majors at a technological university, I have developed an approach that emphasizes the role of moral imagination in conjunction with systems imagination in responding to problems that arise in shared environments. The course is set out on a model of problem-based learning, conceived as a cognitive apprenticeship: by working together to understand and consider responses to problems that are of interest to them, with guidance and tools provided by the instructor, students develop their capacity to notice, respond to and think about systems and values with greater sophistication. After setting out the rationale and the design of the course, I note the challenge that remains: developing a systematic assessment of the course, which would involve detecting and tracking subtle changes in student cognition.

Validation of the Latin American Spanish version of the face-name associative memory exam in a Colombian Sample

Objective The Face-Name Associative Memory Exam (FNAME) has been used to detect subtle cognitive changes in clinically normal older adults at increased risk for Alzheimer’s disease. FNAME assesses learning and delayed recall for face-name pairs. The aim of this study is to introduce a Latin American Spanish version of the FNAME (LAS-FNAME), examine its psychometric properties, and provide preliminary normative data in a sample of clinically normal, Spanish-speaking individuals from Antioquia, Colombia. Method 59 clinically-normal individuals (71% females) were recruited by the Grupo de Neurociencias in Antioquia (Colombia). Age ranged from 27 to 82 years (M = 50.31, SD = 15.32) and years of education ranged from 2 to 17 years (M = 9.02, SD = 4.11). All participants completed the LAS-FNAME and a brief neuropsychological evaluation. We examined associations between age, education, and sex and performance on the LAS-FNAME. Internal consistency, convergent and discriminant validity were also assessed. Test-restest reliability was computed for a subset of participants (n = 32). Results LAS-FNAME exhibited moderate convergent validity with other memory measures (Free and Cued Selective Reminding Scale, r s=.465, p<.01; Wechsler Memory Scale III - Logical Memory Delayed Recall, r s=.479, p<.01). The subscales of the LAS-FNAME exhibited adequate internal consistency (α=.825). Test-retest reliability analyses demonstrated consistency of scores over time. Normative data was stratified by age (<50, 50–65, >65) and low and high educational attainment (≤8 and >8 years of education, respectively). Conclusions The LAS-FNAME is a valid and reliable measure to assess memory in clinically normal, Spanish-speaking individuals from Colombia for clinical and research purposes.