Normal aging and Alzheimer's disease : hippocampal and episodic memory differences

Alzheimer’s Disease (AD) and normal aging (NA) are characterized by structural brain changes as well as cognitive changes that appear over the lifespan. The hippocampus is an area susceptible to early atrophy in both AD and NA; however the differential causes of atrophy are not entirely clear. Hippocampal volume loss in AD is attributed to neuronal death due to underlying pathology. AD often is diagnosed years after the onset of pathology and subsequent atrophy. NA is a continuation of cognitive decline that does not become dementia. Episodic memory (EM) is processed within the hippocampus and is one of the first systems to show deficits in conjunction with both patterns of aging. This review focuses on hippocampal volume loss and EM decline in NA and AD.Communication Sciences and Disorder

Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment

Cortical atrophy is a biomarker of Alzheimer’s disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI

Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer\u27s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Recognition of Famous Names Predicts Cognitive Decline in Healthy Elders

Objective: The ability to recognize familiar people is impaired in both Mild Cognitive Impairment (MCI) and Alzheimer’s Dementia (AD). In addition, both groups often demonstrate a time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently. In this study, we examined the TG in cognitively intact elders for remote famous names (1950–1965) compared to more recent famous names (1995–2005). We hypothesized that the TG pattern on a famous name recognition task (FNRT) would predict future cognitive decline, and also show a significant correlation with hippocampal volume. Method: Seventy-eight healthy elders (ages 65–90) with age-appropriate cognitive functioning at baseline were administered a FNRT. Follow-up testing 18 months later produced two groups: Declining (≥ 1 SD reduction on at least one of three measures) and Stable (\u3c 1 SD). Results: The Declining group (N = 27) recognized fewer recent famous names than the Stable group (N = 51), although recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampi were significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining vs. Stable) independent of chronological age and APOE ε4 inheritance. Conclusions: The TG for famous name recognition may serve as an early preclinical cognitive marker of cognitive decline in healthy older individual

Task-phase fMRI in detection of improvements in working memory post-interventions for carotid stenosis and early Alzheimer’s disease

Working memory allows for coordination of complex goal-driven behavior. Decline of working memory is linked to severe cognitive disabilities and is an important feature of both severe carotid stenosis and Alzheimer\u27s disease. Functional Magnetic Resonance Imaging (fMRI) can help detect functional brain changes for the evaluation of the impact of standard clinical interventions for both diagnoses. This thesis used fMRI, coupled with cognitive tasks to investigate possible working memory improvements post-standard clinical interventions for both conditions. The study observed post-intervention improvements in task-phase fMRI brain activation patterns together with improvements in task performance. Meanwhile, patients demonstrated complex response patterns associated with disease expression and other individual variability, which were considered with results interpretation. This thesis showed that working memory improvements were possible following standard clinical treatments for both conditions. It also supports for tailoring interventions based on patient peculiarities to maximize treatment effectiveness

Medial Temporal Lobe Does Not Tell The Whole Story: Episodic Memory In ‘atypical’ Variants Of Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia, which is globally epidemic and well-known by the general public. Episodic memory, a conscious recollection of a particular event in spatial and temporal context, is the most prominent deficit in the early stage of clinical amnestic AD, and reflected by the shrinkage of structures in medial temporal lobe (MTL), including the hippocampus. According to Braak staging, tangles begin in the transentorhinal cortex of the MTL, which then spreads to hippocampal subfields, and later to neocortical areas. Cases that are less recognized by the general public are patients with the atypical variants of AD. Interestingly, many of the atypical cases of AD appear to share the same histopathological features with clinical amnestic AD. According to the diagnostic criteria for these atypical variants of AD, episodic memory should be relatively preserved. However, inconsistent reports on the episodic memory performance and the hippocampal involvement in these atypical cases pose challenges for accurately diagnosing these patients. The two kinds of atypical variants of AD that I focused here are logopenic variant of Primary Progressive Aphasia (lvPPA) and posterior cortical atrophy (PCA). The overarching theme of my thesis is to examine 1) whether the atypical cases of AD have episodic memory difficulty, and if so, 2) what brain areas are responsible for this difficulty. Chapter 2 and 3 of the current thesis show that 1) episodic memory difficulty is observed in lvPPA and PCA cases and 2) this impairment is modulated by deficit in other cognitive domains and associated with disease in non-MTL brain regions. This would be consistent with the ‘hippocampal-sparing’ hypothesis that not all AD histopathology begins in the MTL, and these hippocampal-sparing conditions suggest that additional mechanisms must be considered in the genesis of spreading pathology in AD

Verbal and visual dissociation in retrieval practice paradigm in neurodegenerative diseases

As is well known, prefrontal functions assert the control of inhibition for the retrieval of semantically related elements that lead to forgetfulness. The aim of this study is to document any verbal and visual dissociation in the Retrieval- Induced Forgetting (RIF). We want to test the hypothesis that representations in long-term visual memory are sufficiently rooted to be immune to impairment based on recognition, unlike oblivion induced by the retrieval of verbal material. The aim of this project is also to investigate which brain areas are most involved in the processes of inhibition and facilitation in patients with different types of cognitive impairment. To do this, 21 patients with Alzheimer's disease (AD), 21 mild cognitive impairment (MCI), 16 patients with subjective cognitive decline (SCD) and 23 healthy subjects (HS) were enrolled. All participants underwent an extensive neuropsychological evaluation by Addenbrooke's Cognitive Examination-Revised (ACE-R; Mioshi et al., 2006) and the Retrieval Practice Paradigm (RPP), with an experimental recognition task, where the same items were presented both in visual and verbal form to calculate, at a group level, the RIF and FAC (facilitation effect) effects. Only subjects who did not have contraindications to perform MRI, (14 AD, 16 MCI, 14 SCD and 18 HS) underwent 3 T-MRI scanning including a T1-w volume. Voxel-based morphometry (VBM) was used to assess associations between grey matter (GM) volumetrics and RPP indices: items practiced by practiced categories (Rp+), items which were not practiced, but were members of the same category as the Rp+ items (Rp-), items which received no additional retrieval practice and were not members of a practiced category (Nrp) in each group separately. ANOVA models were used to assess cross-sectional differences in all neuropsychological measures and experimental conditions and effects. In each of the 4 groups, separately, Pearson's correlations were used to assess potential association between each domain of ACE-R and the three RPP indices (Nrp, RP +, Rp-). Regarding the results about the RPP indices (Nrp, RP +, Rp-), for the verbal task, we observed a significant between-group difference in Nrp items. Post-hoc showed that the proportion of items in the Nrp condition is statistically higher in HS group than AD group. Moreover, we found a significant effect of group in Rp+ items: post-hoc revealed a significant difference between AD and SCD and between AD and HS. Interestingly, the tendency of significance was present on the comparison between AD and MCI. No significant differences were observed between MCI and SCD and between MCI and HS. Similarly, HS and SCD groups showed comparable performance on Rp+ items. Regarding the RPP effects (RIF and FAC), we observed a significant main effect of group in the FAC effect. Post-hoc revealed significant a main effect of group since AD recognized less items than SCD and HS, respetively. We found also a significant main effect of Condition, because the proportion of items retrieved in the Rp+ condition is statistically higher than that retrieved in the Nrp condition in all groups. Finally, we found no significant Group by Condition interaction indicating that the FAC effect was present in all considered groups. Finally, regarding the RIF effect, we observed a significant main effect of group, due to a significant difference exclusively between AD and HS groups; we revealed no significant effect of condition: indeed, in this case the means of item retrieved in two conditions Nrp and Rp- were almost the same. Finally, we found a significant Group by Condition interaction. The planned comparisons showed that the RIF effect was present in the SCD group only, but no RIF effect was observed in AD, in MCI and HS groups. For the visual task, no significant differences were observed between groups in the accuracy of the Nrp items, RP+ items, RP- items. As regards the FAC effect, we observed a significant main effect of group, due to a significant difference exclusively in the recognition of the global accuracy between AD and HS groups. We found also a significant main effect of Condition: in this case, the Rp+ items were better recalled than Nrp items in all groups. Finally, we observed no significant Group by Condition interaction, indicating that the FAC effect was present in all groups. Furthermore, about the RIF effect, in the verbal task, we observed no significant main effect of group, but significant main effect of Condition, since the Nrp items were better remembered than Rp- items. Moreover, we found no significant Group by Condition interaction: in this case, the planned comparisons revealed that the RIF effect was present in the SCD only. Comparing the groups individually, no significant dissociation emerged between two tasks, verbal and visual. There is only a tendency in SCD, due to greater accuracy of subjects who performed the verbal task, compared to those who performed the visual task, in the Rp- condition. For the MRI analysis results, in the Verbal task, VBM results showed in AD patients, revealed a positive association between Rp- items and GM volumes in the Right Putamen, Cingulus Gyrus and Left Putamen. In the Visual task the VBM analyses, revealed in AD patients a positive association between Nrp items and GM volumes in the Middle Frontal Gyrus, Inferior Frontal Gyrus, pars triangularis and Insular Cortex. Moreover, in SCD subjects, a significant positive association were found between Rp- items and GM volumes in the Postcentral Gyrus, Supramarginal Gyrus, Superior Frontal Gyrus, and Precuneous Cortex, bilaterally. In conclusion, in our study, in line with other experiments (Hogge et al., 2008; Saunders and Summers., 2011; Traykov et al., 2011; Ortega et al., 2012; Serra et al., 2022), shows the presence of an inhibitory effect: the RIF is not evident in the pathological group of AD and MCI, but not even in healthy subjects, which generally show good inhibition capacity; this result could be because the recognition task was too simple for healthy subjects, who were able to recall multiple items without distinction. Although there is a trend, in both tasks, in favor of a RIF effect as the pathology increases. We can also hypothesize that the worse performance observed in the RIF obtained from patients is not a direct expression of an inhibitory deficit but could depend on a general deficit of episodic long-term memory processes

Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia

Spatial disorientation is a prominent feature of early Alzheimer's disease (AD) attributed to degeneration of medial temporal and parietal brain regions, including the retrosplenial cortex (RSC). By contrast, frontotemporal dementia (FTD) syndromes show generally intact spatial orientation at presentation. However, currently no clinical tasks are routinely administered to objectively assess spatial orientation in these neurodegenerative conditions. In this study we investigated spatial orientation in 58 dementia patients and 23 healthy controls using a novel virtual supermarket task as well as voxel-based morphometry (VBM). We compared performance on this task with visual and verbal memory function, which has traditionally been used to discriminate between AD and FTD. Participants viewed a series of videos from a first person perspective travelling through a virtual supermarket and were required to maintain orientation to a starting location. Analyses revealed significantly impaired spatial orientation in AD, compared to FTD patient groups. Spatial orientation performance was found to discriminate AD and FTD patient groups to a very high degree at presentation. More importantly, integrity of the RSC was identified as a key neural correlate of orientation performance. These findings confirm the notion that i) it is feasible to assess spatial orientation objectively via our novel Supermarket task; ii) impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and iii) the RSC emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions

Structural anatomical investigation of long-term memory deficit in behavioural frontotemporal dementia

Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34ADpatients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (p(FWE)<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findingsDistALZ CONICET CONICYT/FONDECYT 1170010 1160940 FONCyT, PICT 2012-0412 2012-1309 CONICYT/FONDAP 15150012 INECO Foundatio

The Semantic Memory Imaging In Late Life Pilot Study

Introduction: Several functional magnetic resonance imaging (fMRI) studies have analyzed the famous name discrimination task (FNDT), an uncontrolled semantic memory probe requiring discrimination between famous and unfamiliar individuals. Completion of this simple task recruits a semantic memory network that has shown utility in determining risk for Alzheimer\u27s disease (AD). Specific semantic memory probes using biographical information associated with famous individuals may build on previous findings and yield superior information regarding risk for AD. Method: Sixteen cognitively intact elders completed the FNDT and two novel tasks during fMRI: Categories (matching famous individuals to occupational categories) and Attributes (matching famous individuals to specific bodies of work or life events). Five participants were carriers of the Apolipoprotein E (APOE) ε4 allele. Results: Relative to their respective control tasks, participants recruited brain regions for all three tasks consistent with previous research, including left temporal lobe, left angular gyrus, precuneus, posterior cingulate, and anterior cingulate. The FNDT generated significantly more activity than the other tasks in anterior cingulate and several posterior regions. Categories had significantly lesser activity than other tasks in inferior parietal lobe, precuneus, and posterior cingulate. Attributes, the most specific semantic probe, demonstrated the strongest left lateralization with significantly greater activity in left inferior frontal gyrus and anterior temporal lobe. APOE ε4 carriers had regions with greater activity across all three tasks, with the greatest number of regions for Attributes, including in left anterior temporal lobe. Discussion: This pilot study identified neural correlates of different levels of semantic processing. The FNDT, an unconstrained semantic knowledge probe, demonstrated greater activity across most regions. The Attributes task, a specific semantic probe, had focused left-lateralized activity, including anterior temporal lobe and inferior frontal gyrus. APOE ε4 carriers demonstrated significantly greater activity in left anterior temporal lobe during Attributes only, demonstrating this task\u27s potential utility for determination of AD risk