Short-term memory binding in mild cognitive impairment

We showed that short-term memory (STM) binding is sensitive to sporadic and familial Alzheimer's disease (AD) but is not affected by healthy ageing, chronic depression in the elderly or other forms of dementia. STM binding deficits were also observed in individuals with a genetic susceptibility for AD in the preclinical stages. Hence, we aim to investigate longitudinally individuals with Mild Cognitive Impairment (MCI) using STM binding tasks. Here we report on preliminary cross-sectional results. A comprehensive neuropsychological test battery and a visual STM task were given to 21 MCI patients and 20 controls. The STM task required participants to recognise changes across two consecutive arrays presenting either single features (colour or shape) or feature bindings. The MCI group performed significantly poorer than controls on standard tests of memory, attention and on the binding condition of the STM task, but not on single feature conditions. Performance on the binding task and on standard memory tests did not correlate. Eight MCI patients clearly performed outwith the range of normality in the binding task. However, they did not significantly differ from the other 13 MCI patients in disease severity or demographic and neuropsychological variables. Six patients with binding impairments showed a multiple domain profile whereas ten patients with a preserved binding function showed an amnesic profile [Chi-square = 5.45, p = 0.020]. These results suggest that (1) the binding task is assessing a function different from other memory tests and that (2) STM binding may be differentially impaired in MCI subgroups

A novel peripheral biomarker for mild cognitive impairment and Alzheimer's disease

Background: Recent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short-Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. A combined analysis of oculomotor responses during STMB can enhance the sensitivity of the assessment of patients with AD or at risk of AD such as those with Mild Cognitive Impairment (MCI). We investigated this hypothesis. Methods: Using eye-tracking technologies, we measured pupil dilation, fixation, and exploratory eye movement behaviours in patients with AD, MCI and in healthy controls while they performed the STMBT. The STMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding). Results: Experiment 1 involved 18 healthy older adults and 18 patients with AD dementia. We observed (1) altered pupil dilation linked to poor STMB performance in AD patients. Experiment 2 involved 42 healthy older adults and 63 patients with MCI. Impaired fixation and exploratory eye movement behaviours accompanied poor STMB abilities in MCI patients. Conclusion: Taken together, the results above suggest that eye-tracking measures combined with cognitive markers for AD (STMBT) can (1) enrich the clinical phenotype of this type of dementia, (2) unveil novel features of AD dementia unknown to date, and (2) provide more sensitive tools which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease

Functional assessment of cognitively impaired older adults : are we asking the right questions?

Background: Recent attention has turned to the development of preventative treatments for Alzheimer’s disease (AD) by targeting the early stages of impairment. However, current neuropsychological and functional assessments are not ideally suited to identify early deviations from healthy ageing (HA). The Details of Functions of Everyday Life (DoFEL; Parra & Kaplan, 2019) is a theory-driven scale that incorporates cognitive constructs sensitive to the preclinical stages of dementia (memory binding). DoFEL can help assess the extent to which instrumental functions of daily living are supported by such cognitive abilities and if so, whether by asking the right questions through such a scale we could unveil subtle and still undetected impairments. We predict this would increase the sensitivity of scales to detect older adults with cognitive impairment who are at a high risk of dementia.   Methods: Twenty-five MCI and 21 HA controls (ACE-R score ≥ 88) (Mioshi et al., 2006) underwent an extensive baseline neuropsychological assessment followed by yearly follow-up assessments. The DoFEL is an informant-based neuropsychological assessment that measures a range of functional abilities which rely on different forms of binding functions. This measure includes 82 statements subdivided into 7 functional domains that comprehensively assess different aspects of daily living. Higher DoFEL score indicate greater impairment.   Results: Five key findings from this study were: (1) The total DoFEL score differentiates MCI from HA U=406.00, p=0.002. Higher scores were detected in individuals with MCI (Mdn= 0.41, Mean rank= 29.24) than in the HA (Mdn= 0.35, Mean rank= 16.67). (2) Individuals with MCI showed domain-specific impairments on DoFEL such as Objects and People, Technology and Communication, Work and Social Life. (3) Relative to HA, MCI patients presented with impaired functional abilities that rely on relational (i.e., forming associations, p=0.001) and conjunctive (i.e., forming object identity, p=0.004). (4) DoFEL scores correlate with (r= -0.62, p=0.000), and predicts cognitive performance on the ACE-R (β= -128.68, t(44)= -6.97, p=0.000).   Conclusion: DoFEL can detect differences between individuals with MCI and HA in overall and specific functional abilities seemingly supported by binding functions and therefore may be a useful tool to identify individuals at risk of developing AD

Mosquito-Borne Diseases, Pesticides Used for Mosquito Control, and Development of Resistance to Insecticides

Mosquitoes are one of the most dangerous insects in the world for humanity. Over one million people worldwide die from mosquito-borne diseases every year. Mosquito vectored diseases include protozoan diseases, i.e., malaria, filarial diseases such as dog heartworm, and viral diseases such as dengue, encephalitis, and yellow fever. In addition, mosquitoes transmit several diseases and parasites that dogs and horses are very susceptible too. These include dog heartworm, West Nile virus (WNV), and eastern equine encephalitis (EEE). Since its discovery, chemical insecticides have represented the most widely method used to control mosquito-borne vectors. However, the effects of chemical insecticides on mosquito vector populations are usually transitory because vectors can rapidly develop resistance against them. Each insecticide triggers the selection of one or more mechanisms of resistance. These mechanisms include changes in the target site of action and metabolic detoxification among others

Oculomotor behaviours and integrative memory functions in the Alzheimer's Clinical Syndrome

Background. Biological information drawn from eye-tracking metrics is providing evidence regarding drivers of cognitive decline in Alzheimer disease. In particular, pupil size has proved useful to investigate cognitive performance during online activities. Objective. To investigate the oculomotor correlates of impaired performance of patients with mild Alzheimer’s Clinical Syndrome (ACS) on a recently developed memory paradigm, namely the Short-Term Memory Binding Test (STMBT). Methods. We assessed a sample of eighteen healthy controls (HC) and eighteen patients with a diagnosis of mild ACS with the STMBT while we recorded their oculomotor behaviours using pupillometry and eye-tracking. The STMBT assessed the ability to detected changes across two consecutive visual arrays, study and test, presenting 2 bicolored objects. In one condition, changes consisted of new colours in test objects replacing colours presented in the study objects (i.e., Unbound Colours - UC). In the other condition, changes consisted of two studied colours swapping between objects at test (i.e., Bound Colours - BC). We assessed recognition of such changes. Results. As expected, a group (healthy controls vs Alzheimer’s Clinical Syndrome) by condition (Unbound Colours vs Bound Colours) interaction was found whereby behavioural group differences were paramount in the Bound Colours condition. Healthy control’s pupil dilated significantly more in the Bound Colours than in the Unbound Colours condition, discrepancy not observed in Alzheimer’s Clinical Syndrome patients. Furthermore, ROC analysis revealed the abnormal pupil behaviours distinguished Alzheimer’s Clinical Syndrome patients from healthy controls with values of sensitivity and specify of 100%, thus outperforming both recognition scores and gaze duration. Conclusions. The biological correlates of Short-Term Memory Binding impairments appear to involve a network much wider than we have thought to date, which expands across cortical and subcortical structures. We discuss these findings focusing on their implications for our understanding of neurocognitive phenotypes in the preclinical stages of Alzheimer Disease and potential development of cognitive biomarkers that can support ongoing initiatives to prevent dementia

Oculomotor behaviors and integrative memory functions in the Alzheimer's clinical syndrome

Background: Biological information drawn from eye-tracking metrics is providing evidence regarding drivers of cognitive decline in Alzheimer's disease. In particular, pupil size has proved useful to investigate cognitive performance during online activities. Objective: To investigate the oculomotor correlates of impaired performance of patients with mild Alzheimer’s Clinical Syndrome (ACS) on a recently developed memory paradigm, namely the Short-Term Memory Binding Test (STMBT). Methods: We assessed a sample of eighteen healthy controls (HC) and eighteen patients with a diagnosis of mild ACS with the STMBT while we recorded their oculomotor behaviors using pupillometry and eye-tracking. Results: As expected, a group (healthy controls versus ACS) by condition (Unbound Colours versus Bound Colours) interaction was found whereby behavioral group differences were paramount in the Bound Colours condition. Healthy controls' pupils dilated significantly more in the Bound Colours than in the Unbound Colours condition, a discrepancy not observed in ACS patients. Furthermore, ROC analysis revealed the abnormal pupil behaviors distinguished ACS patients from healthy controls with values of sensitivity and specify of 100%, thus outperforming both recognition scores and gaze duration. Conclusion: The biological correlates of Short-Term Memory Binding impairments appear to involve a network much wider than we have thought to date, which expands across cortical and subcortical structures. We discuss these findings focusing on their implications for our understanding of neurocognitive phenotypes in the preclinical stages of Alzheimer's disease and potential development of cognitive biomarkers that can support ongoing initiatives to prevent dementia

Patterns of brain atrophy in dysexecutive amnestic mild cognitive impairment raise confidence about prodromal AD dementia

Background: Prediction models aimed at detecting risk of progression from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) dementia increase their accuracy when impaired executive functions enter the analysis. This suggests that impaired executive functions in MCI are likely linked to the prodromal stages of AD dementia. Neuroimaging assessment of such patients would allow exploring if they show AD related patterns of brain atrophy. We hypothesized that AD sensitive brain regions would show discrimination between dysexecutive amnestic MCI (maMIC) and healthy controls. Method: We analysed 32 healthy controls and 23 MCI patients. Patients were divided in single domain amnestic MCI, multidomain amnestic MCI (i.e., with the dysexecutive component), and non-amnestic MCI. Brain volume data entered regression models to analyse which brain regions predict group membership (control vs maMCI). Stepwise lineal regression model was then conducted to identify the brain regions with better prediction power. Results: Four variables were able to predict group membership in simple lineal regression models: entorhinal cortex, lingual gyrus and parahippocampal gyrus in the left hemisphere and fusiform gyrus in the right hemisphere. The entorhinal cortex provided the most accurate model (F(1, 42) = 14.19, p=0.001, R2=0.24). Linear regression models were run with performance on executive function tasks including tests of switching, planning, verbal fluency and working memory. The most accurate model returned Letters and Numbers and categories fluency (F(2, 44) = 21.35, p=0.000, R2=0.48) suggesting that working memory and category generation are the functions contributing to the dysexecutive profiles observed in maMCI patients. Conclusion: Dysexecutive profiles in multidomain amnestic MCI together with neuroimaging volumetric analysis increase the probability of identifying the prodromal stages of AD dementia

Graph-Based Permutation Patterns for the Analysis of Task-Related fMRI Signals on DTI Networks in Mild Cognitive Impairment

Permutation Entropy ($PE$) is a powerful nonlinear analysis technique for univariate time series. Very recently, Permutation Entropy for Graph signals ($PE_G$) has been proposed to extend $PE$ to data residing on irregular domains. However, $PE_G$ is limited as it provides a single value to characterise a whole graph signal. Here, we introduce a novel approach to evaluate graph signals at the vertex level: graph-based permutation patterns. Synthetic datasets show the efficacy of our method. We reveal that dynamics in graph signals, undetectable with $PE_G$, can be discerned using our graph-based permutation patterns. These are then validated in the analysis of DTI and fMRI data acquired during a working memory task in mild cognitive impairment, where we explore functional brain signals on structural white matter networks. Our findings suggest that graph-based permutation patterns change in individual brain regions as the disease progresses. Thus, graph-based permutation patterns offer promise by enabling the granular scale analysis of graph signals.Comment: 5 pages, 5 figures, 1 tabl