BACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation. METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants. RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance. CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.
- Keywords
- Allocentric navigation, Amyloid-β, Egocentric navigation, Entorhinal cortex, Hippocampus, Tau protein,
- MeSH
- Alzheimer Disease * genetics cerebrospinal fluid diagnostic imaging complications physiopathology pathology MeSH
- Amyloid beta-Peptides cerebrospinal fluid MeSH
- Apolipoprotein E4 * genetics MeSH
- Apolipoproteins E * genetics MeSH
- Atrophy MeSH
- Biomarkers cerebrospinal fluid MeSH
- Genotype MeSH
- Cognitive Dysfunction * genetics cerebrospinal fluid diagnostic imaging physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain pathology diagnostic imaging MeSH
- Neuropsychological Tests MeSH
- Peptide Fragments cerebrospinal fluid MeSH
- Positron-Emission Tomography MeSH
- Spatial Navigation * physiology MeSH
- tau Proteins cerebrospinal fluid MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- amyloid beta-protein (1-42) MeSH Browser
- Amyloid beta-Peptides MeSH
- Apolipoprotein E4 * MeSH
- Apolipoproteins E * MeSH
- Biomarkers MeSH
- Peptide Fragments MeSH
- tau Proteins MeSH
Spatial reference frames (RFs) play a key role in spatial cognition, especially in perception, spatial memory, and navigation. There are two main types of RFs: egocentric (self-centered) and allocentric (object-centered). Although many fMRI studies examined the neural correlates of egocentric and allocentric RFs, they could not sample the fast temporal dynamics of the underlying cognitive processes. Therefore, the interaction and timing between these two RFs remain unclear. Taking advantage of the high temporal resolution of intracranial EEG (iEEG), we aimed to determine the timing of egocentric and allocentric information processing and describe the brain areas involved. We recorded iEEG and analyzed broad gamma activity (50-150 Hz) in 37 epilepsy patients performing a spatial judgment task in a three-dimensional circular virtual arena. We found overlapping activation for egocentric and allocentric RFs in many brain regions, with several additional egocentric- and allocentric-selective areas. In contrast to the egocentric responses, the allocentric responses peaked later than the control ones in frontal regions with overlapping selectivity. Also, across several egocentric or allocentric selective areas, the egocentric selectivity appeared earlier than the allocentric one. We identified the maximum number of egocentric-selective channels in the medial occipito-temporal region and allocentric-selective channels around the intraparietal sulcus in the parietal cortex. Our findings favor the hypothesis that egocentric spatial coding is a more primary process, and allocentric representations may be derived from egocentric ones. They also broaden the dominant view of the dorsal and ventral streams supporting egocentric and allocentric space coding, respectively.
- Keywords
- Allocentric, Egocentric, High-frequency gamma activity, Intracranial EEG, Reference frames, Spatial judgment,
- MeSH
- Electrocorticography MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Judgment physiology MeSH
- Spatial Processing * MeSH
- Space Perception * physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Spatial navigation impairment is a promising cognitive marker of Alzheimer's disease (AD) that can reflect the underlying pathology. OBJECTIVES: We assessed spatial navigation performance in AD biomarker positive older adults with amnestic mild cognitive impairment (AD aMCI) vs. those AD biomarker negative (non-AD aMCI), and examined associations between navigation performance, MRI measures of brain atrophy, and cerebrospinal fluid (CSF) biomarkers. METHODS: A total of 122 participants with AD aMCI (n = 33), non-AD aMCI (n = 31), mild AD dementia (n = 28), and 30 cognitively normal older adults (CN) underwent cognitive assessment, brain MRI (n = 100 had high-quality images for volumetric analysis) and three virtual navigation tasks focused on route learning (body-centered navigation), wayfinding (world-centered navigation) and perspective taking/wayfinding. Cognitively impaired participants underwent CSF biomarker assessment [amyloid-β1-42, total tau, and phosphorylated tau181 (p-tau181)] and amyloid PET imaging (n = 47 and n = 45, respectively), with a subset having both (n = 19). RESULTS: In route learning, AD aMCI performed worse than non-AD aMCI (p < 0.001), who performed similarly to CN. In wayfinding, aMCI participants performed worse than CN (both p ≤ 0.009) and AD aMCI performed worse than non-AD aMCI in the second task session (p = 0.032). In perspective taking/wayfinding, aMCI participants performed worse than CN (both p ≤ 0.001). AD aMCI and non-AD aMCI did not differ in conventional cognitive tests. Route learning was associated with parietal thickness and amyloid-β1-42, wayfinding was associated with posterior medial temporal lobe (MTL) volume and p-tau181 and perspective taking/wayfinding was correlated with MRI measures of several brain regions and all CSF biomarkers. CONCLUSION: AD biomarker positive and negative older adults with aMCI had different profiles of spatial navigation deficits that were associated with posterior MTL and parietal atrophy and reflected AD pathology.
- Keywords
- allocentric navigation, egocentric navigation, entorhinal cortex, hippocampus, neurodegeneration, precuneus, retrosplenial cortex, tauopathies,
- Publication type
- Journal Article MeSH
BACKGROUND: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. OBJECTIVE: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. METHODS: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). RESULTS: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035). CONCLUSION: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.
- Keywords
- Allocentric spatial navigation, apolipoprotein E, basal forebrain, entorhinal cortex, hippocampus, magnetic resonance imaging, prefrontal cortex,
- MeSH
- Alleles MeSH
- Alzheimer Disease * diagnostic imaging genetics MeSH
- Atrophy MeSH
- Cholinergic Agents MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Basal Forebrain * diagnostic imaging MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cholinergic Agents MeSH
Impairment in spatial navigation (SN) and structural network topology is not limited to patients with Alzheimer's disease (AD) dementia and can be detected earlier in patients with mild cognitive impairment (MCI). We recruited 32 MCI patients (65.91 ± 11.33 years old) and 28 normal cognition patients (NC; 69.68 ± 10.79 years old), all of whom underwent a computer-based battery of SN tests evaluating egocentric, allocentric, and mixed SN strategies and diffusion-weighted and T1-weighted Magnetic Resonance Imaging (MRI). To evaluate the topological features of the structural connectivity network, we calculated its measures such as the global efficiency, local efficiency, clustering coefficient, and shortest path length with GRETNA. We determined the correlation between SN accuracy and network topological properties. Compared to NC, MCI subjects demonstrated a lower egocentric navigation accuracy. Compared with NC, MCI subjects showed significantly decreased clustering coefficients in the left middle frontal gyrus, right rectus, right superior parietal gyrus, and right inferior parietal gyrus and decreased shortest path length in the left paracentral lobule. We observed significant positive correlations of the shortest path length in the left paracentral lobule with both the mixed allocentric-egocentric and the allocentric accuracy measured by the average total errors. A decreased clustering coefficient in the right inferior parietal gyrus was associated with a larger allocentric navigation error. White matter hyperintensities (WMH) did not affect the correlation between network properties and SN accuracy. This study demonstrated that structural connectivity network abnormalities, especially in the frontal and parietal gyri, are associated with a lower SN accuracy, independently of WMH, providing a new insight into the brain mechanisms associated with SN impairment in MCI.
- Keywords
- clustering coefficient, graph theory, mild cognitive impairment, network topology, spatial navigation,
- Publication type
- Journal Article MeSH
Patients with Alzheimer's disease (AD) related dementia and mild cognitive impairment experience difficulties with spatial navigation (SN). However, SN has rarely been investigated in individuals with subjective cognitive decline (SCD), a preclinical stage with elevated progression rate to symptomatic AD. In this study, 30 SCD subjects and 30 controls underwent cognitive scale (CS) evaluation, a 2D computerized SN test, and resting-state functional magnetic resonance imaging scanning. Two SN brain networks (ego-network and allo-network), each with 10 selected spherical regions, were defined. We calculated the average network functional connectivity (FC) and region-to-region FC within the two networks and evaluated correlations with SN performance. Compared with the controls, the SCD group performed worse in the SN test and showed decreased FC between the right retrosplenial and right prefrontal cortices in the ego-network, and between the right retrosplenial cortex and right hippocampus in the allo-network. The logistic regression model based on SN and FC measures revealed a high area under the curve of .880 in differentiating SCD individuals from controls. These results suggest that SN network disconnection contributes to spatial deficits in SCD, and SN and FC measures could benefit the preclinical detection of subjects with incipient AD dementia.
- Keywords
- Allocentric, Egocentric, Functional connectivity, Spatial navigation, Subjective cognitive decline,
- MeSH
- Alzheimer Disease * diagnostic imaging MeSH
- Ego MeSH
- Cognitive Dysfunction * diagnostic imaging MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain MeSH
- Confusion MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Individuals with subjective cognitive decline (SCD) are at higher risk of incipient Alzheimer's disease (AD). Spatial navigation (SN) impairments in AD dementia and mild cognitive impairment patients have been well-documented; however, studies investigating SN deficits in SCD subjects are still lacking. This study aimed to explore whether basal forebrain (BF) and entorhinal cortex (EC) atrophy contribute to spatial disorientation in the SCD stage. In total, 31 SCD subjects and 24 normal controls were enrolled and administered cognitive scales, a 2-dimensional computerized SN test, and structural magnetic resonance imaging (MRI) scanning. We computed the differences in navigation distance errors and volumes of BF subfields, EC, and hippocampus between the SCD and control groups. The correlations between MRI volumetry and navigation distance errors were also calculated. Compared with the controls, the SCD subjects performed worse in both egocentric and allocentric navigation. The SCD group showed volume reductions in the whole BF (p < 0.05, uncorrected) and the Ch4p subfield (p < 0.05, Bonferroni corrected), but comparable EC and hippocampal volumes with the controls. In the SCD cohort, the allocentric errors were negatively correlated with total BF (r = -0.625, p < 0.001), Ch4p (r = -0.625, p < 0.001), total EC (r = -0.423, p = 0.031), and left EC volumes (r = -0.442, p = 0.024), adjusting for age, gender, years of education, total intracranial volume, and hippocampal volume. This study demonstrates that SN deficits and BF atrophy may be promising indicators for the early detection of incipient AD patients. The reduced BF volume, especially in the Ch4p subfield, may serve as a structural basis for allocentric disorientation in SCD subjects independent of hippocampal atrophy. Our findings may have further implications for the preclinical diagnosis and intervention for potential AD patients.
- Keywords
- allocentric, basal forebrain, entorhinal cortex, spatial navigation, subjective cognitive decline,
- Publication type
- Journal Article MeSH
BACKGROUND: Cognitive deficits are common in early multiple sclerosis (MS), however, spatial navigation changes and their associations with brain pathology remain poorly understood. OBJECTIVE: To characterize the profile of spatial navigation changes in two main navigational strategies, egocentric (self-centred) and allocentric (world-centred), and their associations with demyelinating and neurodegenerative changes in early MS. METHODS: Participants with early MS after the first clinical event (n = 51) and age-, gender- and education-matched controls (n = 42) underwent spatial navigation testing in a real-space human analogue of the Morris water maze task, comprehensive neuropsychological assessment, and MRI brain scan with voxel-based morphometry and volumetric analyses. RESULTS: The early MS group had lower performance in the egocentric (p = 0.010), allocentric (p = 0.004) and allocentric-delayed (p = 0.038) navigation tasks controlling for age, gender and education. Based on the applied criteria, lower spatial navigation performance was present in 26-29 and 33-41% of the participants with early MS in the egocentric and the allocentric task, respectively. Larger lesion load volume in cortical, subcortical and cerebellar regions (ß ≥ 0.29; p ≤ 0.032) unlike brain atrophy was associated with less accurate allocentric navigation performance. CONCLUSION: Lower spatial navigation performance is present in up to 41% of the participants with early MS. Demyelinating lesions in early MS may disrupt neural network forming the basis of allocentric navigation.
- Keywords
- Allocentric, Cognition, Egocentric, Lesion load, MRI, Neuropsychology, Volumetry, Voxel-based morphometry,
- MeSH
- Cognition MeSH
- Cognitive Dysfunction * MeSH
- Humans MeSH
- Neuropsychological Tests MeSH
- Spatial Navigation * MeSH
- Multiple Sclerosis * diagnostic imaging MeSH
- Space Perception MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The dissociation between egocentric and allocentric reference frames is well established. Spatial coding relative to oneself has been associated with a brain network distinct from spatial coding using a cognitive map independently of the actual position. These differences were, however, revealed by a variety of tasks from both static conditions, using a series of images, and dynamic conditions, using movements through space. We aimed to clarify how these paradigms correspond to each other concerning the neural correlates of the use of egocentric and allocentric reference frames. We review here studies of allocentric and egocentric judgments used in static two- and three-dimensional tasks and compare their results with the findings from spatial navigation studies. We argue that neural correlates of allocentric coding in static conditions but using complex three-dimensional scenes and involving spatial memory of participants resemble those in spatial navigation studies, while allocentric representations in two-dimensional tasks are connected with other perceptual and attentional processes. In contrast, the brain networks associated with the egocentric reference frame in static two-dimensional and three-dimensional tasks and spatial navigation tasks are, with some limitations, more similar. Our review demonstrates the heterogeneity of experimental designs focused on spatial reference frames. At the same time, it indicates similarities in brain activation during reference frame use despite this heterogeneity.
- MeSH
- Humans MeSH
- Brain Mapping methods MeSH
- Judgment physiology MeSH
- Neuropsychological Tests MeSH
- Attention physiology MeSH
- Spatial Memory physiology MeSH
- Photic Stimulation methods MeSH
- Space Perception physiology MeSH
- Visual Perception physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment in APOEɛ4 carriers but its role in APOEɛ4-related spatial navigation deficits has not been established. OBJECTIVE: We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI). METHODS: 187 participants (aMCI [n = 116] and CU [n = 71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4-/BDNFVal/Val, ɛ4-/BDNFMet, ɛ4+/BDNFVal/Val, and ɛ4+/BDNFMet. The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze. RESULTS: Among the aMCI participants, the ɛ4+/BDNFMet group had the least accurate egocentric navigation performance (p < 0.05) and lower verbal memory performance than the ɛ4-/BDNFVal/Val group (p = 0.007). The ɛ4+/BDNFMet group had smaller hippocampal and entorhinal cortical volumes than the ɛ4-/BDNFVal/Val (p≤0.019) and ɛ4-/BDNFMet (p≤0.020) groups. Among the CU participants, the ɛ4+/BDNFMet group had less accurate allocentric and allocentric delayed navigation performance than the ɛ4-/BDNFVal/Val group (p < 0.05). CONCLUSION: The combination of APOEɛ4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults.
- Keywords
- Alzheimer’s disease, Morris water maze, apolipoproteins E, brain-derived neurotrophic factor, entorhinal cortex, episodic memory, gene polymorphism, magnetic resonance imaging, mild cognitive impairment, spatial navigation,
- MeSH
- Apolipoprotein E4 genetics MeSH
- Cognitive Dysfunction genetics physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Brain-Derived Neurotrophic Factor genetics MeSH
- Polymorphism, Genetic MeSH
- Spatial Navigation physiology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Apolipoprotein E4 MeSH
- BDNF protein, human MeSH Browser
- Brain-Derived Neurotrophic Factor MeSH
