Alzheimer's pathology causes impaired inhibitory connections and reactivation of spatial codes during spatial navigation.
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ABSTRACT:
SUBMITTER: Prince SM
PROVIDER: S-EPMC8139125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.
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Project description:The Mecp2+/- mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivo in RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is accompanied by an enhanced baseline firing synchrony of place cells within ripple oscillations during rest, which consequently occludes the increase in synchrony after a novel experience. Behaviorally, contextual memory is normal at short but not long time scale in RTT mice. Our results suggest that hypersynchrony interferes with memory consolidation and leads to impaired spatial memory codes in RTT mice, providing a possible circuit mechanism for memory deficits in Rett Syndrome.
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Project description:Cerebral small vessel disease (SVD) refers to a heterogeneous group of pathological processes that result from damage to the small penetrating vessels in the brain. Spatial navigation, one of the most fundamental behaviors, has lately attracted considerable clinical interest. This study aimed to determine whether spatial navigation performance is impaired in elderly SVD patients. In total, 18 elderly patients with severe SVD, 40 elderly patients with non-severe SVD, and 41 age-matched healthy volunteers were classified according to the Fazekas scale. Spatial navigation was evaluated by Amunet (a computer-based analogy of Morris water maze software), and a mini-mental scale evaluation (MMSE), animal category verbal fluency test (VFT), clock drawing test (CDT), and trail making test (TMT) -B were also applied. Compared to healthy controls, severe SVD, rather than non-severe SVD patients, exhibited significantly worse performance on "allocentric + egocentric" (41.74 ± 29.10 vs. 31.50 ± 16.47 vs. 29.21 ± 19.03; p = 0.031). Furthermore, the different abilities of spatial navigation among groups reached a statistical level on allocentric subtests (46.93 ± 31.27 vs. 43.69 ± 23.95 vs. 28.56 ± 16.38; p = 0.003), but not on egocentric subtest (56.16 ± 39.85 vs. 56.00 ± 28.81 vs. 43.06 ± 25.07; p = 0.105). The linear regression analysis revealed that allocentric navigation deficit was significantly correlated with TMT-B (p = 0.000, standardized β = 0.342) and VFT (p = 0.016, standardized β = -0.873) performance in elderly SVD patients. These results elucidated that spatial navigation ability could be a manifestation of cognitive deficits in elderly patients with SVD.
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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.
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Project description:Cerebellar activity supported by PKC-dependent long-term depression in Purkinje cells (PCs) is involved in the stabilization of self-motion based hippocampal representation, but the existence of cerebellar processes underlying integration of allocentric cues remains unclear. Using mutant-mice lacking PP2B in PCs (L7-PP2B mice) we here assess the role of PP2B-dependent PC potentiation in hippocampal representation and spatial navigation. L7-PP2B mice display higher susceptibility to spatial map instability relative to the allocentric cue and impaired allocentric as well as self-motion goal-directed navigation. These results indicate that PP2B-dependent potentiation in PCs contributes to maintain a stable hippocampal representation of a familiar environment in an allocentric reference frame as well as to support optimal trajectory toward a goal during navigation.
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Project description:By using AT8-immunocytochemistry that visualizes hyperphosphorylated tau protein, we examined neurofibrillary changes related to sporadic Alzheimer's disease (AD) in N = 40 individuals at neurofibrillary tangle (NFT) stages I-IV. We report the presence of abnormal tau changes within solitary pyramidal neurons in layers III and V of the neocortex. These pyramidal cells showed pathology in different cell compartments (dendritic, somatic, axonal) that appeared to occur sequentially: Tau pathology was seen in distal segments of the basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected neurons. These findings are remarkable in that they point to the existence of neurofibrillary changes in regions routinely associated with later NFT stages. In addition, they lend support to the idea that it may be the axons of cortico-cortical top-down neurons in neocortical fields involved in AD that carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells following directly in the neuronal chain, thereby sustaining further tau-seeded templating.
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Project description:The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer`s disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test-retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable test-retest reliability. Further research in larger sample sizes is desirable.
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Project description:Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer's disease, and even in cognitively normal individuals at risk for Alzheimer's disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer's disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer's disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer's disease.
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Project description:Spatial navigation impairments in Alzheimer's disease (AD) have been suggested to underlie patients experiencing spatial disorientation. Though many studies have highlighted navigation impairments for AD patients in virtual reality (VR) environments, the extent to which these impairments predict a patient's risk for spatial disorientation in the real world is still poorly understood. The aims of this study were to (a) investigate the spatial navigation abilities of AD patients in VR environments as well as in a real world community setting and (b) explore whether we could predict patients at a high risk for spatial disorientation in the community based on their VR navigation. Sixteen community-dwelling AD patients and 21 age/gender matched controls were assessed on their egocentric and allocentric navigation abilities in VR environments using the Virtual Supermarket Test (VST) and Sea Hero Quest (SHQ) as well as in the community using the Detour Navigation Test (DNT). When compared to controls, AD patients exhibited impairments on the VST, SHQ, and DNT. For patients, only SHQ wayfinding distance and wayfinding duration significantly predicted composite disorientation score on the DNT (β = 0.422, p = 0.034, R2 = 0.299 and β = 0.357, p = 0.046, R2 = 0.27 respectively). However, these same VR measures could not reliably predict which patients were at highest risk of spatial disorientation in the community (p > 0.1). Future studies should focus on developing VR-based tests which can predict AD patients at high risk of getting spatially disorientated in the real world.
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Project description:Impairment of navigation is one of the earliest symptoms of Alzheimer's disease (AD), but to date studies have involved proxy tests of navigation rather than studies of real life behaviour. Here we use GPS tracking to measure ecological outdoor behaviour in AD. The aim was to use data-driven machine learning approaches to explore spatial metrics within real life navigational traces that discriminate AD patients from controls. 15 AD patients and 18 controls underwent tracking of their outdoor navigation over two weeks. Three kinds of spatiotemporal features of segments were extracted, characterising the mobility domain (entropy, segment similarity, distance from home), spatial shape (total turning angle, segment complexity), and temporal characteristics (stop duration). Patients significantly differed from controls on entropy (p-value 0.008), segment similarity (p-value [Formula: see text]), and distance from home (p-value [Formula: see text]). Graph-based analyses yielded preliminary data indicating that topological features assessing the connectivity of visited locations may also differentiate patients from controls. In conclusion, our results show that specific outdoor navigation features discriminate AD patients from controls, which has significant implication for future AD diagnostics, outcome measures and interventions. Furthermore, this work illustrates how wearables-based sensing of everyday behaviour may be used to deliver ecologically-valid digital biomarkers of AD pathophysiology.
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