From Morris Water Maze to computer tests in the prediction of Alzheimer's disease.

BACKGROUND: Spatial navigation performance in the Hidden Goal Task (HGT), a real-space human analogue of the Morris Water Maze, can identify amnestic mild cognitive impairment (aMCI) patients with memory impairment of the hippocampal type, a known indicator of incipient Alzheimer's disease (AD). OBJECTIVE: Contrast results from computer versus real-space versions of the HGT. METHODS: A total of 42 aMCI patients were clinically and neuropsychologically classified into: (1) memory impairment of the hippocampal type--the hippocampal aMCI (HaMCI; n = 10) and (2) isolated retrieval impairment--the nonhippocampal aMCI (NHaMCI; n = 32). Results were compared to the control (n = 28) and AD (n = 21) groups. RESULTS: The HaMCI group, although similar to the NHaMCI group with respect to overall cognitive impairment, performed poorer on the computer version of the HGT and yielded parallel results to the real-space version. The two versions were strongly correlated. CONCLUSIONS: Both versions of the HGT can reliably identify aMCI with pronounced memory impairment of the hippocampal type. The computer version of the HGT may be a useful, relatively inexpensive screening tool for early detection of individuals at a high risk of AD.

Human analogue of the morris water maze for testing subjects at risk of Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have difficulties with spatial orientation. OBJECTIVE: To test hypothesis that spatial navigation is impaired early in MCI patients representing the presymptomatic stage of AD. METHODS: We tested patients with probable AD (n = 21), MCI, further classified according to Petersen's criteria as amnestic MCI (aMCI) single domain (n = 11), aMCI multiple domain (n = 31), or nonamnestic MCI (n = 7). The aMCI group was also stratified using cued recall according to Dubois' criteria into memory impairment of the hippocampal type (n = 10) and isolated memory retrieval impairment-nonhippocampal (n = 32) and also according to ApoE4 status into E4+ (n = 12) and E4- (n = 30). These patients and controls (n = 28) were tested in the human variant of the Morris water maze. Depending on the subtest, the subjects could use the egocentric or allocentric (hippocampus-dependent) navigation. RESULTS: The AD and aMCI multiple domain groups were impaired in all subtests. The aMCI single domain group was impaired in allocentric subtests. The hippocampal MCI group performed poorer than the nonhippocampal MCI group and similarly to the AD group. The ApoE4+ group was as bad as the AD group when compared with the E4- group. CONCLUSION: aMCI subjects represent a very heterogeneous population, and spatial memory or cued recall examination can add more value to aMCI classification. ApoE4+ patients are more impaired than ApoE4- patients.

The use of egocentric and allocentric reference frames in static and dynamic conditions in humans.

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.

Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate.

N-methyl-D-aspartate receptors play a critical role in synaptogenesis, synaptic plasticity, and excitotoxicity. They are heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits. The subunit composition determines the biophysical and pharmacological properties of the N-methyl-D-aspartate receptor channel complex. In this study, we report that responses mediated by recombinant rat N-methyl-D-aspartate receptors expressed in human embryonic kidney HEK293 cells are differentially affected by naturally occurring neurosteroid pregnenolone sulfate. We show that responses induced by 1mM glutamate in NR1-1a/NR2A and NR1-1a/NR2B receptors are potentiated five- to eight-fold more by pregnenolone sulfate than responses of NR1-1a/NR2C and NR1-1a/NR2D receptors with no differences in the concentration of pregnenolone sulfate that produced 50% potentiation. In addition to potentiation, pregnenolone sulfate also has an inhibitory effect at recombinant N-methyl-D-aspartate receptors, with values of the concentration of pregnenolone sulfate that produces 50% inhibition of NR1/NR2D=NR1/NR2C

Real-space path integration is impaired in Alzheimer's disease and mild cognitive impairment.

INTRODUCTION: Path integration (PI) is an important component of spatial navigation that integrates self-motion cues to allow the subject to return to a starting point. PI depends on the structures affected early in the course of Alzheimer's disease (AD) such as the medial temporal lobe and the parietal cortex. OBJECTIVES: To assess whether PI is impaired in patients with mild AD and amnestic mild cognitive impairment (aMCI) and to investigate the role of the hippocampus, entorhinal and inferior parietal cortex in this association. METHODS: 27 patients with aMCI, 14 with mild AD and 18 controls completed eight trials of Arena Path Integration Task. The task required subjects with a mask covering their eyes to follow an enclosed triangle pathway through two previously seen places: start-place1-place2-start. Brains were scanned at 1.5T MRI and respective volumes and thicknesses were derived using FreeSurfer algorithm. RESULTS: Controlling for age, education, gender and Mini-Mental State Examination score the aMCI and AD subjects were impaired in PI accuracy on the pathway endpoint (p=0.042 and p=0.013) compared to controls. Hippocampal volume and thickness of entorhinal and parietal cortices explained separately 36-45% of the differences in PI accuracy between controls and aMCI and 28-31% of the differences between controls and AD subjects. CONCLUSIONS: PI is affected in aMCI and AD, possibly as a function of neurodegeneration in the medial temporal lobe structures and the parietal cortex. PI assessment (as a part of spatial navigation testing) may be useful for identification of patients with incipient AD.

[Severe lead intoxication after ingestion of lead shots]. / Tezká otrava olovem po pozití broku.

The authors describe severe lead intoxication in a male patient who swallowed about 20 lead shots by accident. It caused an acute lead intoxication with highest blood lead reaching about 2.4 fold value of biological exposure limit for blood lead concentration for occupational exposure (0.97 mg/l), coproporphyrines in urine reaching 30 fold increase of biological exposure limit (1000 nmol/mmol creatinine), and 5-aminolevulic acid about 2.7 fold increase of biological limit (35.0 micromol/mmol creatinine). After first dose of chelating antidote (calcium disodium edetate, EDTA) the patient excreted 9.0 mg of lead in urine during 24 hours. Clinical symptoms and results of examinations led to suspicion of gastroduodenal ulcer at first. Diagnosis was defined after detailed examination and completing of the patient's history. Typical symptoms of intoxication developed--normocytic normochromic anemia and saturnine colics. Elimination of shots from digestive tract and treatment with 8 doses of antidote led to crucial change and improvement in the course of one month. The article should serve as an instruction to early recognition of lead intoxication.

Intracellular spermine decreases open probability of N-methyl-D-aspartate receptor channels.

Spermine and related polyamines have been shown to be endogenous regulators of several ion channel types including ionotropic glutamate receptors. The effect of spermine on N-methyl-d-aspartate (NMDA) receptors in cultured rat hippocampal neurons was studied using single-channel and whole-cell patch clamp recordings. Intracellular spermine resulted in the dose-dependent inhibition of NMDA-induced responses. Spermine reversibly inhibited the single NMDA receptor channel activity in inside-out patches suggesting a membrane-delimited mechanism of action. Open probability of NMDA receptor channels was decreased in a dose-dependent manner. Mechanism of spermine-induced inhibition of NMDA receptor was different from that of intracellular Ca(2+)-induced NMDA receptor inactivation. Both pharmacological studies and single channel analysis indicate that in contrast to the effect of extracellular spermine the intracellular spermine effect is not dependent on the NMDA receptor subunit composition. We propose that intracellular spermine has a direct inhibitory effect on NMDA receptors that is different from calcium-induced NMDA receptor inactivation and spermine-induced voltage-dependent inhibition of AMPA/kainate receptors. Spermine-induced tonic change in the open probability of NMDA receptor channels may play a role in mechanisms underlying short-term changes in the synaptic efficacy.

Spatial navigation: implications for animal models, drug development and human studies.

Spatial navigation and memory is considered to be a part of the declarative memory system and it is widely used as an animal model of human declarative memory. However, spatial tests typically involve only static settings, despite the dynamic nature of the real world. Animals, as well as people constantly need to interact with moving objects, other subjects or even with entire moving environments (flowing water, running stairway). Therefore, we design novel spatial tests in dynamic environments to study brain mechanisms of spatial processing in more natural settings with an interdisciplinary approach including neuropharmacology. We also translate data from neuropharmacological studies and animal models into development of novel therapeutic approaches to neuropsychiatric disorders and more sensitive screening tests for impairments of memory, thought, and behavior.