Hippocampal dysfunction is associated with memory impairment in multiple sclerosis: A volumetric and functional connectivity study

BACKGROUND: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients OBJECTIVE: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. METHODS: hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (MSi and MSp, respectively) and healthy controls. A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp and MSi. RESULTS: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi>MSp>HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. CONCLUSIONS: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).This study was sponsored by grants P1-1B2014-15 awarded by Universitat Jaume I and PSI2015-67285-R awarded by MINECO to Dr. Cristina For

Neural correlates of cognitive intervention in persons at risk of developing Alzheimer's disease.

Cognitive training is an emergent approach that has begun to receive increased attention in recent years as a non-pharmacological, cost-effective intervention for Alzheimer's disease (AD). There has been increasing behavioral evidence regarding training-related improvement in cognitive performance in early stages of AD. Although these studies provide important insight about the efficacy of cognitive training, neuroimaging studies are crucial to pinpoint changes in brain structure and function associated with training and to examine their overlap with pathology in AD. In this study, we reviewed the existing neuroimaging studies on cognitive training in persons at risk of developing AD to provide an overview of the overlap between neural networks rehabilitated by the current training methods and those affected in AD. The data suggest a consistent training-related increase in brain activity in medial temporal, prefrontal, and posterior default mode networks, as well as increase in gray matter structure in frontoparietal and entorhinal regions. This pattern differs from the observed pattern in healthy older adults that shows a combination of increased and decreased activity in response to training. Detailed investigation of the data suggests that training in persons at risk of developing AD mainly improves compensatory mechanisms and partly restores the affected functions. While current neuroimaging studies are quite helpful in identifying the mechanisms underlying cognitive training, the data calls for future multi-modal neuroimaging studies with focus on multi-domain cognitive training, network level connectivity, and individual differences in response to training

Measurement of allocentric processing in mild cognitive impairment and early Alzheimer’s disease using a virtual reality object location paradigm

Aim: Mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) are major contributors to disability in old age and defined in the early stages by spatial memory deficits associated with hippocampal (HC) and entorhinal (EC) atrophy. Currently diagnosis occurs late in the process which limits efficacy of interventions. This study investigated the neural correlates of a novel object location task (OLT) in immersive virtual reality (iVR). Methods: Twenty amnestic MCI (aMCI) patients and twenty two healthy controls were tested on the iVR OLT, underwent neuropsychological testing and structural MRI scanning. OLT performance and HC, EC subfield volumetric data were compared between groups, and correlational analyses of HC/EC volumes and performance were conducted. Results: Participants with aMCI were significantly impaired in object location recall and object recognition compared to controls. They had significantly smaller total HC, subiculum, CA1, EC and perirhinal volumes. There was a significant interaction of group in analysis of neural correlates: OLT performance was strongly predicted by total HC and subiculum volumes in patients only. EC subfields were not significant predictors of performance. Conclusion: Performance on the novel OLT in immersive VR is a good indicator of HC integrity in older adults with amnestic MCI and can improve the diagnostic process for people with MCI and AD in the future

The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan

Background: The hippocampus is an important limbic structure closely related to memory function. However, few studies have focused on the association between hippocampal subfields and age-related memory decline. We investigated the volume alterations of hippocampal subfields at different ages and assessed the correlations with Immediate and Delayed recall abilities.Materials and Methods: A total of 275 participants aged 20–89 years were classified into 4 groups: Young, 20–35 years; Middle-early, 36–50 years; Middle-late, 51–65 years; Old, 66–89 years. All data were acquired from the Dallas Lifespan Brain Study (DLBS). The volumes of hippocampal subfields were obtained using Freesurfer software. Analysis of covariance (ANCOVA) was performed to analyze alterations of subfield volumes among the 4 groups, and multiple comparisons between groups were performed using the Bonferroni method. Spearman correlation with false discovery rate correction was used to investigate the relationship between memory recall scores and hippocampal subfield volumes.Results: Apart from no significant difference in the left parasubiculum (P = 0.269) and a slight difference in the right parasubiculum (P = 0.022), the volumes of other hippocampal subfields were significantly different across the adult lifespan (P < 0.001). The hippocampal fissure volume was increased in the Old group, while volumes for other subfields decreased. In addition, Immediate recall scores were associated with volumes of the bilateral molecular layer, granule cell layer of the dentate gyrus (GC-DG), cornus ammonis (CA) 1, CA2/3, CA4, left fimbria and hippocampal amygdala transition area (HATA), and right fissure (P < 0.05). Delayed recall scores were associated with the bilateral molecular layer, GC-DG, CA2/3 and CA4; left tail, presubiculum, CA1, subiculum, fimbria and HATA (P < 0.05).Conclusion: The parasubiculum volume was not significantly different across the adult lifespan, while atrophy in dementia patients in some studies. Based on these findings, we speculate that volume changes in this region might be considered as a biomarker for dementia disorders. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the key role of the hippocampus in age-related memory decline. These regions could be used to assess the risk of memory decline across the adult lifespan

Behavioural and neural characteristics of navigation impairments in preclinical Alzheimer’s disease

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk preclinical individuals. This thesis focuses on spatial navigation deficits, which are increasingly shown to be present in atrisk individuals, because the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Experimental chapters 2 and 3, show that a novel test battery captures navigation deficits that precede the onset of verbal and non-verbal episodic memory deficits in preclinical disease and that resting-state functional connectivity between the EC and the PCC underpins such deficits. Evidence for moderate test re-test reliability in the same non-clinical sample is presented in chapter 4. Moving beyond detection of preclinical disease, and towards prevention, in chapter 5 we examined whether marine fish oils help preserve the volume of AD vulnerable brain regions and found that low circulating DHA blood concentration predicts preservation of hippocampal and entorhinal volume in preclinical AD. This is potentially due to increased DHA uptake from the blood to the brain due to preclinical disease. Taken together, the research advances our conceptual understanding of the pathological and compensatory changes that characterise preclinical AD and offers important information toward generating more accurate risk profiles for AD vulnerable adults

Imaging of cognitive outcomes in patients with autoimmune encephalitis

Die Autoimmunenzephalitis ist eine kürzlich beschriebene entzündliche Erkrankung des zentralen Nervensystems, die Gedächtnisdefizite, Psychosen, oder epileptische Anfälle hervorrufen kann. Derzeit ist hingegen noch nicht ausreichend verstanden, welche pathologischen Veränderungen zu den kognitiven Defiziten führen und welche neuropsychologischen und bildgebenden Langzeitoutcomes zu erwarten sind. Anhand von strukturellen und funktionellen Bildgebungsanalysen zeigt diese Dissertation, dass kognitive Defizite auch nach der akuten Phase der Autoimmunenzephalitis fortbestehen können. Bei der LGI1-Enzephalitis gehen Gedächtnisdefizite mit fokalen strukturellen Läsionen im Hippocampus einher. Durch eine funktionelle Störung der Resting-State-Konnektivität des Default-Mode- und Salienznetzwerkes beeinträchtigen diese Hippocampusläsionen auch Hirnregionen außerhalb des limbischen Systems. Bei Patient:innen mit NMDA-Rezeptor-Enzephalitis finden sich in der longitudinalen neuropsychologischen Untersuchung trotz guter allgemeiner Genesung auch noch mehrere Jahre nach der Akutphase persistierende Defizite des Gedächtnisses und exekutiver Funktionen. Zuletzt zeigt eine transdiagnostische Analyse, dass der anteriore Hippocampus eine erhöhte Vulnerabilität gegenüber immunvermittelten pathologischen Prozessen aufweist. Diese Ergebnisse legen nahe, dass kognitive Symptome auch noch nach der Entlassung aus der stationären Behandlung fortbestehen können. Sowohl umschriebene strukturelle Hippocampusläsionen als auch Veränderungen in makroskopischen funktionellen Hirnnetzwerken tragen zur pathophysiologischen Erklärung dieser Symptome bei. Zudem erlauben diese Ergebnisse einen Einblick in neuroplastische Veränderungen des Gehirns und haben weitreichende Implikationen für die Langzeitversorgung und das Design zukünftiger klinischer Studien.Autoimmune encephalitis is a recently described inflammatory disease of the central nervous system that can cause memory deficits, psychosis, or seizures. The trajectory of cognitive dysfunction and the underlying long-term imaging correlates are, however, not yet fully understood. By using advanced structural and functional neuroimaging, this thesis shows that cognitive deficits persist beyond the acute phase. In LGI1 encephalitis, MRI postprocessing revealed that memory deficits are related to focal structural hippocampal lesions. These hippocampal lesions propagate to brain areas outside the limbic system through aberrant resting-state connectivity of the default mode network (DMN) and the salience network. In NMDA receptor encephalitis, a longitudinal analysis of neuropsychological data describes persistent cognitive deficits, especially in the memory and executive domains, despite good physical recovery several years after the acute disease. Lastly, a transdiagnostic analysis reveals that the anterior hippocampus is particularly vulnerable to immune-mediated damage. In conclusion, these results demonstrate that cognitive symptoms in autoimmune encephalitis can persist beyond discharge from neurological care. Both discrete structural hippocampal damage and changes in macroscopic functional networks shed light on the pathophysiological basis of these symptoms. These findings help to explain how the brain responds to pathological damage and have substantial implications for long-term patient care and the design of future clinical studies

Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia

MRI Asymmetry Index of Hippocampal Subfields Increases Through the Continuum From the Mild Cognitive Impairment to the Alzheimer's Disease

Objective: It is well-known that the hippocampus presents significant asymmetry in Alzheimer's disease (AD) and that difference in volumes between left and right exists and varies with disease progression. However, few works investigated whether the asymmetry degree of subfields of hippocampus changes through the continuum from Mild Cognitive Impairment (MCI) to AD. Thus, aim of the present work was to evaluate the Asymmetry Index (AI) of hippocampal substructures as possible MRI biomarkers of Dementia. Moreover, we aimed to assess whether the subfields presented peculiar differences between left and right hemispheres. We also investigated the relationship between the asymmetry magnitude in hippocampal subfields and the decline of verbal memory as assessed by Rey's auditory verbal learning test (RAVLT).Methods: Four-hundred subjects were selected from ADNI, equally divided into healthy controls (HC), AD, stable MCI (sMCI), and progressive MCI (pMCI). The structural baseline T1s were processed with FreeSurfer 6.0 and volumes of whole hippocampus (WH) and 12 subfields were extracted. The AI was calculated as: (|Left-Right|/(Left+Right))*100. ANCOVA was used for evaluating AI differences between diagnoses, while paired t-test was applied for assessing changes between left and right volumes, separately for each group. Partial correlation was performed for exploring relationship between RAVLT summary scores (Immediate, Learning, Forgetting, Percent Forgetting) and hippocampal substructures AI. The statistical threshold was Bonferroni corrected p < 0.05/13 = 0.0038.Results: We found a general trend of increased degree of asymmetry with increasing severity of diagnosis. Indeed, AD presented the higher magnitude of asymmetry compared with HC, sMCI and pMCI, in the WH (AI mean 5.13 ± 4.29 SD) and in each of its twelve subfields. Moreover, we found in AD a significant negative correlation (r = −0.33, p = 0.00065) between the AI of parasubiculum (mean 12.70 ± 9.59 SD) and the RAVLT Learning score (mean 1.70 ± 1.62 SD).Conclusions: Our findings showed that hippocampal subfields AI varies differently among the four groups HC, sMCI, pMCI, and AD. Moreover, we found—for the first time—that hippocampal substructures had different sub-patterns of lateralization compared with the whole hippocampus. Importantly, the severity in learning rate was correlated with pathological high degree of asymmetry in parasubiculum of AD patients