David López-Sanz

Alpha band disruption in the AD-continuum starts in the Subjective Cognitive Decline stage: a MEG study

The consideration of Subjective Cognitive Decline (SCD) as a preclinical stage of AD remains still a matter of debate. Alpha band alterations represent one of the most significant changes in the electrophysiological profile of AD. In particular, AD patients exhibit reduced alpha relative power and frequency. We used alpha band activity measured with MEG to study whether SCD and MCI elders present these electrophysiological changes characteristic of AD, and to determine the evolution of the observed alterations across AD spectrum. The total sample consisted of 131 participants: 39 elders without SCD, 41 elders with SCD and 51 MCI patients. All of them underwent MEG and MRI scans and neuropsychological assessment. SCD and MCI patients exhibited a similar reduction in alpha band activity compared with the no SCD group. However, only MCI patients showed a slowing in their alpha peak frequency compared with both SCD and no SCD. These changes in alpha band were related to worse cognition. Our results suggest that AD-related alterations may start in the SCD stage, with a reduction in alpha relative power. It is later, in the MCI stage, where the slowing of the spectral profile takes place, giving rise to objective deficits in cognitive functioning.

Network Disruption in the Preclinical Stages of Alzheimer’s Disease: From Subjective Cognitive Decline to Mild Cognitive Impairment

INTRODUCTION Subjective Cognitive Decline (SCD) is a largely unknown state thought to represent a preclinical stage of Alzheimers Disease (AD) previous to mild cognitive impairment (MCI). However, the course of network disruption in these stages is scarcely characterized. METHODS We employed resting state magnetoencephalography in the source space to calculate network smallworldness, clustering, modularity and transitivity. Nodal measures (clustering and node degree) as well as modular partitions were compared between groups. RESULTS The MCI group exhibited decreased smallworldness, clustering and transitivity and increased modularity in theta and beta bands. SCD showed similar but smaller changes in clustering and transitivity, while exhibiting alterations in the alpha band in opposite direction to those showed by MCI for modularity and transitivity. At the node level, MCI disrupted both clustering and nodal degree while SCD showed minor changes in the latter. Additionally, we observed an increase in modular partition variability in both SCD and MCI in theta and beta bands. CONCLUSION SCD elders exhibit a significant network disruption, showing intermediate values between HC and MCI groups in multiple parameters. These results highlight the relevance of cognitive concerns in the clinical setting and suggest that network disorganization in AD could start in the preclinical stages before the onset of cognitive symptoms.

Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations

Functional connectivity (FC) alterations represent a key feature in Alzheimers Disease (AD) and provide a useful tool to characterize and predict the course of the disease. Those alterations have been also described in Mild Cognitive Impairment (MCI), a prodromal stage of AD. There is a growing interest in detecting AD pathology in the brain in the very early stages of the disorder. Subjective Cognitive Decline (SCD) could represent a preclinical asymptomatic stage of AD but very little is known about this population. In the present work we assessed whether FC disruptions are already present in this stage, and if they share any spatial distribution properties with MCI alterations (a condition known to be highly related to AD). To this end, we measured electromagnetic spontaneous activity with MEG in 39 healthy control elders, 41 elders with SCD and 51 MCI patients. The results showed FC alterations in both SCD and MCI compared to the healthy control group. Interestingly, both groups exhibited a very similar spatial pattern of altered links: a hyper-synchronized anterior network and a posterior network characterized by a decrease in FC. This decrease was more pronounced in the MCI group. These results highlight that elders with SCD present FC alterations. More importantly, those disruptions affected AD typically related areas and showed great overlap with the alterations exhibited by MCI patients. These results support the consideration of SCD as a preclinical stage of AD and may indicate that FC alterations appear very early in the course of the disease.

Choice of Magnetometers and Gradiometers after Signal Space Separation

Background: Modern Elekta Neuromag MEG devices include 102 sensor triplets containing one magnetometer and two planar gradiometers. The first processing step is often a signal space separation (SSS), which provides a powerful noise reduction. A question commonly raised by researchers and reviewers relates to which data should be employed in analyses: (1) magnetometers only, (2) gradiometers only, (3) magnetometers and gradiometers together. The MEG community is currently divided with regard to the proper answer. Methods: First, we provide theoretical evidence that both gradiometers and magnetometers result from the backprojection of the same SSS components. Then, we compare resting state and task-related sensor and source estimations from magnetometers and gradiometers in real MEG recordings before and after SSS. Results: SSS introduced a strong increase in the similarity between source time series derived from magnetometers and gradiometers (r2 = 0.3–0.8 before SSS and r2 > 0.80 after SSS). After SSS, resting state power spectrum and functional connectivity, as well as visual evoked responses, derived from both magnetometers and gradiometers were highly similar (Intraclass Correlation Coefficient > 0.8, r2 > 0.8). Conclusions: After SSS, magnetometer and gradiometer data are estimated from a single set of SSS components (usually ≤ 80). Equivalent results can be obtained with both sensor types in typical MEG experiments.

APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults

BACKGROUND Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimers disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs. OBJECTIVE The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. METHODS Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. RESULTS The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group. CONCLUSION Genetic profile modulates training outcomes in sentence comprehension.

The Role of Magnetoencephalography in the Early Stages of Alzheimer’s Disease

The ever increasing proportion of aged people in modern societies is leading to a substantial increase in the number of people affected by dementia, and Alzheimer’s Disease (AD) in particular, which is the most common cause for dementia. Throughout the course of the last decades several different compounds have been tested to stop or slow disease progression with limited success, which is giving rise to a strong interest toward the early stages of the disease. Alzheimer’s disease has an extended an insidious preclinical stage in which brain pathology accumulates slowly until clinical symptoms are observable in prodromal stages and in dementia. For this reason, the scientific community is focusing into investigating early signs of AD which could lead to the development of validated biomarkers. While some CSF and PET biomarkers have already been introduced in the clinical practice, the use of non-invasive measures of brain function as early biomarkers is still under investigation. However, the electrophysiological mechanisms and the early functional alterations underlying preclinical Alzheimer’s Disease is still scarcely studied. This work aims to briefly review the most relevant findings in the field of electrophysiological brain changes as measured by magnetoencephalography (MEG). MEG has proven its utility in some clinical areas. However, although its clinical relevance in dementia is still limited, a growing number of studies highlighted its sensitivity in these preclinical stages. Studies focusing on different analytical approaches will be reviewed. Furthermore, their potential applications to establish early diagnosis and determine subsequent progression to dementia are discussed.

Efficacy of Cognitive Training in Older Adults with and without Subjective Cognitive Decline Is Associated with Inhibition Efficiency and Working Memory Span, Not with Cognitive Reserve

The present study explores the role of cognitive reserve, executive functions, and working memory (WM) span, as factors that might explain training outcomes in cognitive status. Eighty-one older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline or cognitively intact. Each participant underwent a neuropsychological assessment that was conducted both at baseline (entailing cognitive reserve, executive functions, WM span and depressive symptomatology measures, as well as the Mini-Mental State Exam regarding initial cognitive status), and then 6 months later, once each participant had completed the training program (Mini-Mental State Exam at the endpoint). With respect to cognitive status the training program was most beneficial for subjective cognitive decline participants with low efficiency in inhibition at baseline (explaining a 33% of Mini-Mental State Exam total variance), whereas for cognitively intact participants training gains were observed for those who presented lower WM span.

Functional brain networks reveal the existence of cognitive reserve and the interplay between network topology and dynamics

We investigated how the organization of functional brain networks was related to cognitive reserve (CR) during a memory task in healthy aging. We obtained the magnetoencephalographic functional networks of 20 elders with a high or low CR level to analyse the differences at network features. We reported a negative correlation between synchronization of the whole network and CR, and observed differences both at the node and at the network level in: the average shortest path and the network outreach. Individuals with high CR required functional networks with lower links to successfully carry out the memory task. These results may indicate that those individuals with low CR level exhibited a dual pattern of compensation and network impairment, since their functioning was more energetically costly to perform the task as the high CR group. Additionally, we evaluated how the dynamical properties of the different brain regions were correlated to the network parameters obtaining that entropy was positively correlated with the strength and clustering coefficient, while complexity behaved conversely. Consequently, highly connected nodes of the functional networks showed a more stochastic and less complex signal. We consider that network approach may be a relevant tool to better understand brain functioning in aging.

Scoping Review of Neuroimaging Studies Investigating Frailty and Frailty Components

Background: Neuroimaging techniques are a cornerstone for diagnosing and investigating cognitive decline and dementia in the elderly. In frailty research, the physical as opposed to the cognitive domain of the aging process, neuroimaging studies are less common. Here we systematically review the use of neuroimaging techniques in frailty research. Methods: We searched PUBMED for any publication reporting the association between neuroimaging markers and frailty, following Frieds original definition, as well as its determining phenotypes: gait speed, grip strength, fatigue and recent weight loss in the non-diseased population older than 65 years. Results: The search returned a total of 979 abstracts which were independently screened by 3 reviewers. In total, 17 studies met the inclusion criteria. Of these, 12 studies evaluated gait speed, 2 grip strength, and 3 frailty (2 Fried Frailty, 1 Frailty Index). An association between increased burden of white matter lesions, lower fractional anisotropy, and higher diffusivity has been associated consistently to frailty and worse performance in the different frailty components. Conclusions: White matter lesions were significantly associated to frailty and frailty components thus highlighting the potential utility of neuroimaging in unraveling the underlying mechanisms of this state. However, considering small sample size and design effects, it is not possible to completely rule out reverse causality between frailty and neuroimaging findings. More studies are needed to clarify this important clinical question.

Physical activity effects on the individual alpha peak frequency of older adults with and without genetic risk factors for Alzheimer’s Disease: A MEG study

OBJECTIVE Since a cure for Alzheimers Disease (AD) is yet to be discovered, attention has shifted towards prevention. Physical activity (PA) emerged as a notorious lifestyle factor that could influence brain structure and function. The individual alpha peak frequency (IAPF) is a measure that summarizes the spectral content of brain signals and has been proven to be sensitive to both AD pathology and PA interventions. Therefore, our goal was to unravel whether chronic PA modulates IAPF and if APOE ɛ4 carriage moderates this relationship. METHODS We analyzed 4-minutes of resting-state magnetoencephalographic recordings from 100 healthy elders that provided self-reported measures of PA, and the IAPF was calculated. RESULTS We found that IAPF was negatively influenced by age and APOE and positively influenced by PA. The effect of PA on IAPF only remained significant for the ɛ4 non-carriers group. CONCLUSIONS PA is positively associated to higher IAPF in healthy older adults and could potentially act as a protective factor against cognitive decline. Nevertheless, such effect is non-significant among elders who are more vulnerable to developing AD due to their genetic carriage. SIGNIFICANCE This investigation offers the first neurophysiological evidences on the combined effects of APOE genotype and PA in healthy elders.