A large body of research has investigated various aspects of attention in normal aging and Alzheimers disease (AD). Most of the previous studies have shown that divided attention, the ability to attend to two tasks or stimuli simultaneously, declines in both normal aging and AD. In a recent study of attention, Baddeley, Baddeley, Bucks, and Wilcock (2001) reported findings that contrast with other divided attention research. Specifically, they found no effects of aging on divided attention. Taken in combination with their findings of age and AD effects on other aspects of attention, the authors concluded that age-equivalent results on divided attention tasks support the theory that attentional control should be viewed as a fractionated system. Study 1 considered methodological differences between the divided attention tasks used by Baddeley et al., and the tasks used by researchers who have reported age-related differences. Specifically, the effects of task difficulty on age effects were examined. Young, middle-aged, and older adults were compared on a dual-task procedure that combined a secondary visuomotor task (box joining) with a primary verbal task (month reciting) administered at two levels of difficulty. Results showed a significant Age x Task Difficulty interaction. That is, differences among age groups were proportionately greater in the difficult dual-task condition versus the easy condition, suggesting that age-related declines in divided attention may only be detected if tasks are sufficiently difficult.<p> Study 2 examined attention in normal aging and AD. Young adults, older adults, and early-stage AD patients were compared on tasks of selective attention, focal attention, and divided attention, with each task administered at two levels of difficulty. Similar Group x Task Difficulty interaction effects were detected for all attentional tasks, a finding which is more consistent with a general-purpose model than a fractionated model of attention. Study 3 considered attentional tasks from a clinical perspective. Specifically, the attentional tasks utilized in Study 2 were examined with respect to their ability to correctly classify individuals with early-stage AD and normal older adults. Findings showed that all attentional tasks successfully discriminated patients from cognitively healthy older adults, with one task of divided attention showing particularly impressive sensitivity and specificity. Findings of the three studies are discussed with regard to their implications for future research and clinical practice.

A large body of research has investigated various aspects of attention in normal aging and Alzheimers disease (AD). Most of the previous studies have shown that divided attention, the ability to attend to two tasks or stimuli simultaneously, declines in both normal aging and AD. In a recent study of attention, Baddeley, Baddeley, Bucks, and Wilcock (2001) reported findings that contrast with other divided attention research. Specifically, they found no effects of aging on divided attention. Taken in combination with their findings of age and AD effects on other aspects of attention, the authors concluded that age-equivalent results on divided attention tasks support the theory that attentional control should be viewed as a fractionated system. Study 1 considered methodological differences between the divided attention tasks used by Baddeley et al., and the tasks used by researchers who have reported age-related differences. Specifically, the effects of task difficulty on age effects were examined. Young, middle-aged, and older adults were compared on a dual-task procedure that combined a secondary visuomotor task (box joining) with a primary verbal task (month reciting) administered at two levels of difficulty. Results showed a significant Age x Task Difficulty interaction. That is, differences among age groups were proportionately greater in the difficult dual-task condition versus the easy condition, suggesting that age-related declines in divided attention may only be detected if tasks are sufficiently difficult.<p> Study 2 examined attention in normal aging and AD. Young adults, older adults, and early-stage AD patients were compared on tasks of selective attention, focal attention, and divided attention, with each task administered at two levels of difficulty. Similar Group x Task Difficulty interaction effects were detected for all attentional tasks, a finding which is more consistent with a general-purpose model than a fractionated model of attention. Study 3 considered attentional tasks from a clinical perspective. Specifically, the attentional tasks utilized in Study 2 were examined with respect to their ability to correctly classify individuals with early-stage AD and normal older adults. Findings showed that all attentional tasks successfully discriminated patients from cognitively healthy older adults, with one task of divided attention showing particularly impressive sensitivity and specificity. Findings of the three studies are discussed with regard to their implications for future research and clinical practice.

No description available.

Myelin damage is known to increase in the normal aging brain and to correlate with age-related cognitive decline. While the causes of increased myelin damage are unknown, here we consider whether the brain’s innate capacity for remyelination diminishes with age and hence could contribute to myelin damage through slow accumulation of myelin defects. Maintenance and repair of myelin depends upon oligodendroglia precursor cells (OPCs), which must differentiate into a sufficient number of healthy mature oligodendroglia (oligos), the myelinating cell of the brain. The extracellular matrix molecule hyaluronic acid (HA) has been shown to inhibit maturation of OPCs into mature myelinating oligos. The present study examined aging changes in myelination using four markers: the damaged myelin basic protein (dMBP) antibody, a histochemical reaction to stain HA, and immunohistochemistry for OPCs and mature oligos. These markers were quantified using cell density (oligos and OPCs), percent area stained (HA and dMBP), and fluorescence intensity (HA and dMBP). Relationships between these markers, age, and behavioral measures of cognitive function were investigated using single and multiple regression analyses. Results showed that in the corpus callosum and cingulum bundle of the rhesus monkey, staining for dMBP as a marker of myelin damage strongly correlated with increases in HA. The increase in HA in the cingulum bundle correlated positively with age. OPC density increased with age in both the cingulum bundle and corpus callosum. Mature oligo density did not change significantly with age, but approached a significant increase in the cingulum and approached a significant decrease in the corpus callosum. The increase in OPC density correlated positively with both HA and dMBP in the cingulum bundle. These data are consistent with the hypothesis that HA accumulation contributes to myelin damage by inhibiting the differentiation of OPCs into mature oligodendrocytes, diminishing the brain’s innate capacity for remyelination with age.

In many regions worldwide, older adults now form the fastest growing portion of the population. As such, aging research has seen tremendous growth in recent years, with a focus on identifying early biomarkers of age-related disease. However, crucial to understanding age-related disease is to identify what constitutes normal brain aging, and the life-course factors associated with positive outcomes in later life. In support of this goal, the current dissertation is comprised of three manuscripts that aim to investigate the functional and structural correlates of normal aging in a sample of community-dwelling younger and older adults, from both a multimodal and multi-analysis perspective. Study 1: The first study examined how cumulative cardiovascular risk and self-reported levels of physical, social, and cognitive activity are associated with differences in hippocampal volumes in early and later adulthood. Results indicated that greater cumulative cardiovascular risk was associated with smaller hippocampal volumes across age cohorts. Moreover, a negative association found between frequency of social activities and bilateral hippocampal volumes in older adults, suggesting that social activities with a low cognitive load may not be beneficial to structural brain outcomes in older age. Study 2: This study employed novel advances in functional magnetic resonance imaging (fMRI) to study fluctuations in the blood-oxygen-level dependent (BOLD) signal in relation to age and markers of brain health. Specifically, the study examined the relationship between resting-state BOLD variability and markers of both vascular health and lifestyle activity levels. Results indicated that resting-state BOLD variability is increased in older relative to younger adults. The findings also suggest that the association between BOLD variability and lifestyle activity levels may differ depending on age. Study 3: The final study aimed to further investigate the origins of the BOLD variability signal by examining the feasibility of combining functional near infrared spectroscopy (fNIRS) with fMRI brain signal fluctuation data. In addition to providing proof of concept of combining fNIRS hemoglobin metrics with fMRI BOLD variability maps, the results of this study also indicate that the patterns of regional association between resting hemoglobin concentrations and BOLD fluctuations may vary according to age cohort. Together, the three studies comprising this dissertation illustrate the value of adopting a multimodal, life-course perspective in the study of normal aging. These findings also support increasing evidence of a relationship between the BOLD variability signal and age. Given the limitations of cross-sectional designs for demonstrating change over time, longitudinal investigations with larger sample sizes across multiple age groups are needed to further the development of public health measures aimed at promoting successful aging from early adulthood. / Graduate / 2022-12-08

OBJECTIVE: To determine whether volumetric measures of the hippocampus or entorhinal cortex in combination with other cortical measures can differentiate between cognitively normal individuals and participants with amnestic mild cognitive impairment (MCI). METHODS: T1-weighted magnetic resonance imaging (MRI) data acquired from 46 cognitively normal participants and 50 participants with amnestic MCI as part of the Boston University Alzheimer's Disease Center research registry and the Alzheimer's Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical and subcortical volumes, including hippocampal subfield volumes, were automatically generated from each participant’s structural MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to evaluate their ability to identify participants with MCI. RESULTS: A model containing 11 regions of interest (insula, superior parietal cortex, rostral middle frontal cortex, middle temporal cortex, pars opercularis, paracentral lobule, whole hippocampus, subiculum, superior temporal cortex, precentral cortex and caudal anterior cingulate cortex) fit the data best (R2 = 0.7710, whole model test chi square = 102.4794, p < 0.0001). CONCLUSIONS: Volumetric measures acquired from MRI were able to correctly identify most healthy control subjects and those with amnestic MCI using measures of selected medial temporal lobe structures in combination with those from other cortical areas yielding an overall classification of 95.83% for this dataset. These findings support the notion that while clinical features of amnestic MCI may reflect medial temporal atrophy, differences that can be used to distinguish between these two populations are present elsewhere in the brain. This finding further affirming that atrophy can be identified before clinical features are expressed. Additional studies are needed to assess how well other imaging modalities, such as resting state functional connectivity, diffusion imaging, and amyloid and tau position emission tomography (PET), perform in classifying participants who are cognitively normal versus those who are amnestic MCI.

The normal aging process in humans is characterized by a number of hallmark changes including decreased white matter volume in the brain and accompanying cognitive decline. This is in contrast to neurodegenerative aging processes which involve acute pathology which results in neuronal cell death. Studying non-degenerative normal aging in humans can be difficult because of the high prevalence of neurodegenerative diseases in the population and other potentially confounding effects. Rhesus monkeys are an excellent model organism for the study of normal aging, as their aging process has been demonstrated to involve diminished white matter volume, but they do not suffer from neurodegenerative diseases such as Alzheimer's. In this study we seek to quantify levels of myelin degradation using confocal microscopy in regions of interest where it has been previously demonstrated that loss of white matter integrity results in lower levels of cognitive function across different treatment groups including aging monkeys, calorie restricted monkeys, and controls for calorie restricted monkeys. These areas include prefrontal white matter which is vital to executive function, the hippocampus which is integral to memory consolidation and the learning process, and finally the anterior, middle, and posterior cingulum bundle. The cingulum bundle contains a diverse variety of projections between cortical and subcortical regions, including but not limited to projections to and from the cingulate cortex which has been demonstrated to be vital for emotional processing, the limbic system, and a wide spectrum of other functions. We aim to quantify white matter degradation in these regions by using immunofluorescent tagging for healthy myelin basic protein (MBP) and degraded myelin basic protein (dMBP) and by measuring the colocalization between the two. For prefrontal white matter and hippocampus, we did not find significant differences in myelin degradation across treatment groups. In the cingulum bundle, however, we did find a significant effect of treatment on overall myelin damage throughout the bundle, and in particular we determined that there was a significant difference in colocalization in the anterior cingulum bundle between aging monkeys and control calorie restricted monkeys. Analysis of behavioral testing data yielded surprising results as we were unable to find a strong correlation between our measure for myelin degradation, and level of cognitive impairment. Our results indicate that there are likely differences in regional vulnerability to age related myelin damage across different white matter regions of the brain, however we would like to expand on this study to gain a more accurate understanding of how loss of white matter volume is distributed through the brain and the impact that has on cognitive outcomes.

Le vieillissement, normal ou pathologique, s’accompagne de déficits marqués de la mémoire épisodique et de la mémoire de travail. Dès lors, est-il possible d’optimiser l’apprentissage moteur en s’appuyant sur d’autres registres de mémoire éventuellement moins affectés, voire épargnés, par les effets du temps ? Dans les trois expériences que nous avons menées, la prédominance d’un registre de mémoire sur un autre a été manipulée en contrastant les effets, lors de la réalisation de 160 essais d’une tâche sensorimotrice (le putting au golf), de deux méthodes distinctes d’apprentissage : la méthode en condition d’erreurs fréquentes supposée solliciter les processus mnésiques déclaratifs (mémoire épisodique et mémoire de travail) vs la méthode en condition d’erreurs peu fréquentes supposée solliciter les processus mnésiques procéduraux. Dans l’Étude 1, nous avons testé, chez des adultes jeunes et âgés, l’efficacité de ces méthodes et la nature des processus en jeu lors de la réalisation simultanée d’une tâche secondaire coûteuse en attention. Dans l’Étude 2, nous avons comparé les performances motrices entre des adultes jeunes, plus âgés, et des patients Alzheimer. Dans l’Étude 3, nous avons évalué les effets de la verbalisation des actions motrices produites durant l’apprentissage sur les processus mnésiques sous-tendant la performance motrice d’adultes jeunes et plus âgés. Les résultats de l’Étude 1 montrent que l’apprentissage est affecté par le vieillissement lorsque prédominent les processus déclaratifs mais qu’il est préservé des effets du temps lorsque prédominent les processus procéduraux. Les résultats de l’Étude 2 démontrent que l’apprentissage est préservé des effets de la maladie d’Alzheimer lorsque prédominent les processus procéduraux. Les résultats de l’Étude 3 révèlent que la verbalisation affecte les processus déclaratifs mais n’a pas d’effet sur les processus procéduraux chez les adultes jeunes et qu’elle n’a aucun effet sur ces deux types de processus chez les adultes plus âgés. Ces résultats attestent qu’il est possible de « contourner » la mémoire déclarative et les déficits survenant avec l’âge ou avec la maladie en s’appuyant sur une mémoire procédurale intacte, ce qui a pour effet d’optimiser l’apprentissage moteur. / Normal or pathological aging is characterized by specific deficits in episodic and working memories. Therefore, is it possible to optimize motor learning with advancing age, by utilizing other memory processes hypothesized to be less affected or even spared from aging? We conducted three experiments in which the predominance of one memory system over another was manipulated by contrasting the effects, across 160 trials of a sensorimotor task (golf putting), of two different learning methods: the infrequent-error method hypothesized to primarily rely upon declarative memory vs. the frequent–error method hypothesized to primarily rely upon procedural memory. In Experiment 1, we tested in young and older adults the efficiency of these methods and the nature of processes involved when a secondary, attention-demanding task was performed concurrently. In Experiment 2, we compared the motor performance between young and older adults and Alzheimer patients. In Experiment 3, we assessed the effects of verbalizing previous motor actions produced during learning on processes underlying young and older adults’ motor performance. The results of Experiment 1 showed that learning is affected by aging when declarative processes are predominant but is protected from advancing age when procedural processes are predominant. The results of Experiment 2 demonstrated that learning is preserved from Alzheimer’s disease when procedural processes are predominant. The results of Experiment 3 revealed that verbalization affects declarative processes but has no effect on procedural processes in young adults, and that it has no effect on these two types of processes in older adults. Altogether, these results show that “bypassing” declarative memory and its deficits occurring with advancing age or disease is doable by utilizing intact procedural memory, thus leading to an optimized motor learning.

Lors du vieillissement sain, et malgré une augmentation de la fréquence d’apparition du manque du mot, les personnes âgées manifestent une préservation des performances de dénomination orale d’objets (DO), suggérant la mise en place de stratégies efficaces de récupération et de sélection de l’information lexicale. Dans ce travail de thèse, nous avons utilisé une approche méthodologique multimodale afin d’évaluer la nature de ces stratégies. Nous nous sommes plus spécifiquement intéressés aux mécanismes de réorganisation cérébrale ainsi qu’aux activités sociales comme facteur de réserve cognitive. Ce travail de thèse se décompose en cinq études et aborde une perspective homogène (effet de l’âge) et hétérogène (effet des performances) du vieillissement. Nos résultats mettent en évidence l’existence de différents mécanismes de compensation associés au vieillissement sain. Tout d’abord, nous observons que les personnes âgées sont plus lentes que les jeunes adultes lors de la DO, mais obtiennent un taux de précision similaire. D’après la perspective homogène, le maintien des performances de DO s’expliquerait par le recrutement d’une stratégie de nature sémantique. Au niveau cérébral, nous observons une augmentation de l’asymétrie intra-hémisphérique gauche des régions temporo-pariétales chez les personnes âgées, ainsi qu’un transfert de la connectivité normalement observée du gyrus frontal inférieur (GFI) gauche avec le gyrus temporal latéral au gyrus temporal médial gauche. D’après la perspective hétérogène, le maintien des performances de DO s’expliquerait par l’utilisation d’une stratégie de nature exécutive, reflétée par une réduction de l’asymétrie inter-hémisphérique frontale chez les personnes âgées dont les temps de réponse de DO sont courts. Par ailleurs, nous proposons que l’encodage lexico-phonologique module également le taux de précision de DO, via la connectivité effective entre le GFI gauche et le gyrus temporal supérieur gauche. Enfin, nous observons une relation significative entre la fréquence de participation aux activités sociales, notamment collectives, et les performances de DO. Cette relation est partiellement médiée au niveau cérébral par l’activité du gyrus frontal supérieur médian gauche, via un mécanisme de réserve neurale. Sur la base de nos résultats, nous proposons un modèle neurocognitif des stratégies de récupération et de sélection de l’information lexicale, utilisant une approche multimodale et plurifactorielle du vieillissement sain. / Despite increased difficulties to find words in the daily life, older adults show preserved object naming performances when compared to younger ones. This suggests a supplementary recruitment of compensatory strategies in order to retrieve and select words. In this research work, we have used a multimodal methodological approach to evaluate the nature of these strategies, by using an object naming task. Specifically, we have evaluated these strategies in terms of mechanisms of cerebral reorganization. We were also interested to know how these strategies are modulated by the frequency of social activities, considered as a factor of cognitive reserve. This thesis work is composed of five studies performed under a homogeneous (effect of age) and a heterogeneous (effect of performance) perspective. Based on results, we suggest that aging is associated with multiple compensatory mechanisms to maintain a correct level of performance. Specifically, according to the homogeneous perspective, we consider that preserved object naming performances in older adults might be explained by the use of a semantic strategy. Indeed, in older compared to younger adults and at a cerebral level, we observed increased left hemispheric asymmetry with significant recruitment of the temporo-parietal regions. In addition, the inferior frontal gyrus (IFG) that is connected to the lateral temporal cortex in younger adults, seems to “switch” its connectivity toward the left medial temporal gyrus in older adults. In addition, according to the heterogeneous perspective, preserved object naming performances in older adults can be also explained by the use of an executive strategy, reflected by reduced inter-hemispheric asymmetry of frontal regions, specifically in more performant older adults (with shorter response latencies). Furthermore, we suggest that lexico-phonological processes mediate naming accuracy as reflected by the increased connectivity from the left IFG to the left superior temporal gyrus. A final result that we report in this work indicates that the frequency of participation to group social activities correlates to naming performance in older adults. This relation is partially mediated by the left superior medial frontal gyrus and is assimilated to a neural reserve mechanism. Overall, based on our findings, we propose a neurocognitive model of lexical retrieval and selection strategies in normal aging, based on a multimodal dataset and a multifactorial approach.

Dans le contexte actuel du vieillissement de la population, il importe de s’intéresser aux changements qui surviennent avec l’avancement en âge. Le vieillissement s’accompagne de modifications pour différentes fonctions cognitives, dont la mémoire de travail (MdeT), un système permettant le maintien temporaire et la manipulation d’une petite quantité d’informations. Les travaux de cette thèse portent sur le vieillissement normal de la MdeT et des fonctions de contrôle attentionnel (FCA) qui la sous-tendent (l’alternance, l’inhibition et la mise à jour). D’abord, la première étude (Chapitre II) visait à préciser l’effet du vieillissement normal sur la MdeT et sur chacune des FCA qui la sous-tendent. Elle avait également pour but d’identifier les FCA qui contribuent à la réalisation de différentes tâches de MdeT, et si cette contribution diffère selon le groupe d’âge. Des tâches mesurant chacune des FCA ainsi que des tâches de MdeT ont été administrées à des personnes âgées et à des jeunes adultes. Les analyses contrôlant pour le ralentissement cognitif ont révélé que les habiletés d’alternance et de mise à jour sont préservées chez les personnes âgées, mais que l’inhibition est atteinte comparativement aux jeunes adultes. Les analyses ont également montré que l’impact du vieillissement sur la MdeT dépend de la tâche utilisée. Enfin, les résultats ont indiqué que la contribution des FCA à la MdeT dépend à la fois de la tâche de MdeT et du groupe d’âge. En particulier, la mise à jour contribue davantage à la MdeT des personnes âgées qu’à celle des jeunes, ce qui pourrait refléter une tentative de compensation. La seconde étude (Chapitre III) avait pour objectif de caractériser la variabilité interindividuelle au niveau des FCA, pour les personnes âgées et pour les jeunes adultes. Des analyses hiérarchiques en grappes réalisées sur les habiletés d’alternance, d’inhibition et de mise à jour, ont permis de déterminer si différents profils de contrôle attentionnel étaient présents. L’étude cherchait également à déterminer si les individus appartenant à des profils de contrôle attentionnel distincts diffèrent quant à certaines variables intellectuelles ou de santé. Les analyses ont mis en évidence trois profils de contrôle attentionnel distincts parmi les personnes âgées, l’inhibition étant une FCA critique pour distinguer entre les trois sous-groupes. Trois profils de contrôle attentionnel ont également été identifiés chez les jeunes adultes, et ces profils étaient caractérisés par moins de variabilité intra-individuelle que ceux des âgés. Les analyses ont par ailleurs montré que les profils de contrôle attentionnel se distinguent sur certaines variables intellectuelles et de santé. Les implications théoriques et cliniques de ces résultats seront discutées en fin de thèse (Chapitre IV). / As the population is aging, it is increasingly important to study the changes that occur with advancing age. Normal aging is characterized by changes in various cognitive functions, such as working memory (WM), a limited capacity system that temporarily holds and manipulates a small quantity of information. The work presented in this thesis focused on the normal aging of WM and of the attentional control functions (ACFs) that underlie this system (shifting, inhibition, and updating). The first study (Chapter II) aimed at exploring the impact of normal aging on WM and on each of the ACFs. We also sought to determine which ACFs contribute to performance on different WM tests, and whether age group has an impact on those contributions. Tasks measuring each ACF as well as WM tasks were administered to healthy older adults and to younger adults. The analyses controlling for cognitive slowing revealed that older adults’ shifting and updating abilities are preserved, but that their inhibition abilities are impaired compared to younger adults. Moreover, the impact of normal aging on WM is task-dependent. The results also indicated that the relative contribution of the ACFs to WM depends on both the WM task used and the age group. In particular, older adults relied more than younger adults on updating to perform WM tasks, which might reflect a compensation attempt. The second study (Chapter III) aimed at characterizing interindividual variability in the ACFs of both older and younger adults. Cluster analyses were performed on the shifting, inhibition, and updating abilities, in order to determine whether different attentional control profiles were present. This study also explored whether the individuals that belonged to distinct attentional control profiles differed as to intellectual and health variables. The analyses revealed three attentional control profiles among older adults, and inhibition was the ACF for which the three profiles differed the most. Three attentional control profiles were also identified among younger adults, and their profiles were characterized by less intra-individual variability than those of older adults. The results also showed that individuals belonging to different attentional control profiles differed on some intellectual and health variables. The theoretical and clinical implications of those findings are discussed in Chapter IV.