Getting lost in Alzheimer’s disease: A break in the mental frame syncing

Despite the clinical significance of topographical disorientation in Alzheimer’s disease, it is not clear which cognitive spatial processes are primarily impaired. Here, we argue that a deficit in “mental frame syncing” between egocentric and allocentric spatial representations causes early manifestations of topographical disorientation in AD. Specifically, patients show impairment in translating from an allocentric hippocampal representation to an egocentric parietal one for the purpose of effective spatial orientation and navigation. We suggest that a break in “mental frame syncing”, underpinned by damage to the hippocampus and retrosplenial cortex, may be a crucial cognitive marker both for early and differential diagnosis of AD. Identification of these spatial deficits could facilitate the development of early cognitive rehabilitation interventions and the possibility of identifying individuals most at risk for progression to AD during the preclinical stages.     

Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice

Navigation deficits are prominent in Alzheimer's disease (AD) patients and transgenic mice expressing familial AD-mutant hAPP and A beta peptides. To determine the impact of strategy use on these deficits, we assessed hAPP and nontransgenic mice in a cross maze that can be solved by allocentric (world-based) or egocentric (self-based) strategies. Most nontransgenic mice used allocentric strategies, whereas half of hAPP mice were egocentric. At 3 months, all mice learned the cross maze rapidly; at 6 months, only allocentric hAPP mice were impaired. At 3 and 6 months, hAPP mice had reduced hippocampal Fos expression, which correlated with cross maze learning in older mice. Striatal pCREB expression was unaltered in hAPP mice, suggesting striatal sparing. We conclude that egocentric strategy use may be an earlier indicator of hAPP/A beta-induced hippocampal impairment than spatial learning deficits. Persistent use of allocentric strategies when egocentric strategies are available is maladaptive when there is hippocampal damage. Interventions promoting flexibility in selecting learning strategies might help circumvent otherwise debilitating navigational deficits caused by AD-related hippocampal dysfunction.     

Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: Insights from imaging and behavioral studies

Normal aging and mild Alzheimer's disease (AD) are associated with declines in navigational skills, including allocentric and egocentric representations, cognitive mapping, landmark processing, and spatial memory. These changes, however, are associated with different patterns of structural and functional alterations in the neural network of navigation. In AD, these changes occur in the hippocampus, parahippocampal gyrus, parietal lobe, retrosplenial cortex, prefrontal cortex, and caudate nucleus, whereas in aging, modifications occur mainly in the prefrontal cortex and the hippocampus. The navigation abilities of patients with mild cognitive impairment (MCI) have been found to show different performance patterns, depending on their cognitive profiles. Since patients with MCI do not uniformly develop dementia of the Alzheimer type, it is important to identify reliable early cognitive markers of conversion to AD dementia. In this review, we propose that navigation deficits may help distinguish patients at higher risk of developing AD dementia from individuals with normal cognitive aging and those with other neurodegenerative diseases.     

Prefrontal serotonin depletion impairs egocentric, but not allocentric working memory in rats

Working memory is a cognitive ability chiefly organized by the prefrontal cortex. Working memory tests may be resolved based on allocentric or egocentric spatial strategies. Serotonergic neurotransmission is closely involved in working memory, but its role in spatial strategies for working memory performance is unknown. To address this issue, prefrontal serotonin depletion was induced to adult male rats, and three days after the behavioral expression of both allocentric and egocentric strategies were evaluated in the "Y" maze and in a crossed-arm maze, respectively. Serotonin depletion caused no effects on allocentric-related behavioral performance, but lesioned rats performed deficiently when the egocentric working memory was evaluated. These results suggest that serotonin may be more closely related with the organization of working memory that uses own movement-guided responses than with that involving the use of external visuospatial signals. Further neurochemical studies are needed to elucidate possible interactions between serotonergic activity and other neurotransmitter systems in the organization of working memory-related allocentric and egocentric strategies.     

Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory

Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory, the lesion data to date have been equivocal. Whether subjects are impaired after retrosplenial lesions seems to depend on whether the lesions were aspirative or excitotoxic, with the latter failing to produce an impairment. A shortcoming of previous excitotoxic lesion studies is that they spared the most caudal part of the retrosplenial cortex. The present study thus used rats with extensive neurotoxic lesions of the retrosplenial cortex that encompassed the entire rostrocaudal extent of this region. These rats were consistently impaired on several tests that tax allocentric memory. In contrast, they were unimpaired on an egocentric discrimination task. Although the lesions did not appear to affect object recognition, clear deficits were found for an object-in-place discrimination. The present study not only demonstrates a role for the retrosplenial cortex in allocentric spatial memory, but also explains why previous excitotoxic lesions have failed to detect any deficits.     

Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (< 75 years) and shorter follow-up intervals (< 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.     

Gender differences in the cognitive impairment in Alzheimer's disease

Summary Introduction: There is evidence for gender differences in cognitive functioning. Men and women with Alzheimer's disease (AD) might also differ in the pattern of cognitive deficits. We hypothesised that gender differences in the cognitive deficits of Alzheimer's disease may be related to pre-existing gender differences in cognitive functioning. Method: The performances of 84 subjects with AD and 438 non-demented elderly, using the structured interview for the diagnosis of dementia of the Alzheimer type, multi-infarct dementia and dementias of other aetiology according to ICD-10 and DSM-III-R (SIDAM), were investigated. Subscores for different cognitive functions were compared between men and women. Confounding variables, i.e. age, degree of cognitive impairment, level of education, presence of lifetime diagnosis of major depression and of recent depressive symptoms, were accounted for by multiple regression analyses. Results: Non-demented elderly women had inferior visuoconstructive skills than men. In agreement, women with Alzheimer's disease also had inferior visuoconstructive skills, but in addition they tended to perform worse in items for intellectual abilities than men. Conclusion: Women seem to have minor weaknesses in spatial thinking compared to men. This may explain the inferior test results of non-demented and demented women in visuoconstructive tasks. However, our data also give some evidence for additional domain specific gender differences of cognitive impairment of AD that could not be observed in non-demented elderly, i.e. inferior test results in items for intellectual abilities in demented women compared with demented men. Gender differences in the neurodegenerative process of AD may add to gender differences in domain specific cognitive impairment. Further research on this topic is needed.     

The haptic perception of spatial orientations

This review examines the isotropy of the perception of spatial orientations in the haptic system. It shows the existence of an oblique effect (i.e., a better perception of vertical and horizontal orientations than oblique orientations) in a spatial plane intrinsic to the haptic system, determined by the gravitational cues and the cognitive resources and defined in a subjective frame of reference. Similar results are observed from infancy to adulthood. In 3D space, the haptic processing of orientations is also anisotropic and seems to use both egocentric and allocentric cues. Taken together, these results revealed that the haptic oblique effect occurs when the sensory motor traces associated with exploratory movement are represented more abstractly at a cognitive level.     

Memory for visuospatial location following selective hippocampal sclerosis: the use of different coordinate systems

This study addressed the role of the medial temporal lobe regions and, more specifically, the contribution of the human hippocampus in memory for body-centered (egocentric) and environment-centered (allocentric) spatial location. Twenty-one patients with unilateral atrophy of the hippocampus secondary to long-standing epilepsy (left, n = 7; right, n = 14) and 15 normal control participants underwent 3 tasks measuring recall of egocentric or allocentric spatial location. Patients with left hippocampal sclerosis were consistently impaired in the allocentric conditions of all 3 tasks but not in the egocentric conditions. Patients with right hippocampal sclerosis were impaired to a lesser extent and in only 2 of the 3 tasks. It was concluded that hippocampal structures are crucial for allocentric, but not egocentric, spatial memory.     

Beyond memory impairment: cognitive changes in Alzheimer's disease.

In addition to memory impairment, deficits in other cognitive processes are common in the advanced stages of Alzheimer's disease (AD). The diagnosis of AD does not consider the relative prevalence of deficits in cognitive areas other than memory. We report on the prevalence of aphasia, apraxia, and other cognitive changes in individuals from a large representative sample of elderly Canadians. The proportion of these symptoms and the relevant neuropsychological test performance were compared in a group of 749 people over 65 years in age with AD and a control group of 563 people without cognitive impairment. Agnosia was less common in both groups than were deficits in complex visuomotor tasks, abstract thinking, aphasia, and constructional defects. The occurrence of all symptoms increased, and levels of performance on relevant neuropsychological tests decreased, with severity of Alzheimer disease. The tests did not, however, distinguish between possible and probable AD. Both these diagnostic groups showed similar levels of performance, which suggests that this distinction is not clinically meaningful.     

The neural basis of egocentric and allocentric coding of space in humans: a functional magnetic resonance study

The spatial location of an object can be represented in the brain with respect to different classes of reference frames, either relative to or independent of the subject's position. We used functional magnetic resonance imaging to identify regions of the healthy human brain subserving mainly egocentric or allocentric (object-based) coordinates by asking subjects to judge the location of a visual stimulus with respect to either their body or an object. A color-judgement task, matched for stimuli, difficulty, motor and oculomotor responses, was used as a control. We identified a bilateral, though mainly right-hemisphere based, fronto-parietal network involved in egocentric processing. A subset of these regions, including a much less extensive unilateral, right fronto-parietal network, was found to be active during object-based processing. The right-hemisphere lateralization and the partial superposition of the egocentric and the object-based networks is discussed in the light of neuropsychological findings in brain-damaged patients with unilateral spatial neglect and of neurophysiological studies in the monkey.     

Restriction of early exploratory forays effects specific aspects of spatial processing in weanling hamsters

Normally reared hamsters, but not hamsters reared on a liquid diet, demonstrated spatial memory for the location of odor cues in an allocentric task (Experiment 1). In Experiment 2, an egocentric task, liquid-reared hamsters detected a change in the spatial location of odor cues. In Experiment 3 liquidreared hamsters detected a change in the spatial location of two visual cues under allocentric task conditions. Female hamsters on a liquid diet retrieved their pups more often than dams on solid food, resulting in reduced exploratory opportunities for their pups during the period when olfaction mediates behavior. Hamsters in Experiment 4 experienced a direct restriction of early forays. The restricted-rearing group failed to detect a change in the spatial location of odor cues in an allocentric task. These findings suggest that restriction of early exploratory experience during a narrow period of development results in specific spatial processing deficits.     

Double dissociation of egocentric and allocentric space following medial prefrontal and parietal cortex lesions in the rat

Animals with medial prefrontal cortex or parietal cortex lesions and sham-operated and non-operated controls were tested for the acquisition of an adjacent arm task that accentuated the importance of egocentric spatial localization and a cheese board task that accentuated the importance of allocentric spatial localization. Results indicated that relative to controls, animals with medial-prefrontal cortex lesions are impaired on the adjacent arm task but displayed facilitation on the cheese board task. In contrast, relative to controls, rats with parietal cortex lesions are impaired on the cheese board task but show no impairment on the adjacent arm task. The data suggest a double dissociation of function between medial prefrontal cortex and parietal cortex in terms of coding of egocentric versus allocentric spatial information.     

Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides,cognition, and treatment strategies

Alzheimer's disease (AD) is the most common form of degenerative dementia and is characterized by progressive impairment in cognitive function during mid- to late-adult life. Brains from AD patients show several distinct neuropathological features, including extracellular beta-amyloid-containing plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated tau, and degeneration of cholinergic neurons of the basal forebrain. In this review, we will present evidence implicating involvement of the basal forebrain cholinergic system in AD pathogenesis and its accompanying cognitive deficits. We will initially discuss recent results indicating a link between cholinergic mechanisms and the pathogenic events that characterize AD, notably amyloid-beta peptides. Following this, animal models of dementia will be discussed in light of the relationship between basal forebrain cholinergic hypofunction and cognitive impairments in AD. Finally, past, present, and future treatment strategies aimed at alleviating the cognitive symptomatology of AD by improving basal forebrain cholinergic function will be addressed.     

Functional neuroimaging findings in healthy middle-aged adults at risk of Alzheimer’s disease

It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility.     

A body-centred frame of reference drives spatial priming in visual search

Spatial priming in visual search is a well-documented phenomenon. If the target of a visual search is presented at the same location in subsequent trials, the time taken to find the target at this repeated target location is significantly reduced. Previous studies did not determine which spatial reference frame is used to code the location. At least two reference frames can be distinguished: an observer-related frame of reference (egocentric) or a scene-based frame of reference (allocentric). While past studies suggest that an allocentric reference frame is more effective, we found that an egocentric reference frame is at least as effective as an allocentric one (Ball et al. Neuropsychologia 47(6):1585–1591, 2009). Our previous study did not identify which specific egocentric reference frame was used for the priming: participants could have used a retinotopic or a body-centred frame of reference. Here, we disentangled the retinotopic and body-centred reference frames. In the retinotopic condition, the position of the target stimulus, when repeated, changed with the fixation position, whereas in the body-centred condition, the position of the target stimulus remained the same relative to the display, and thus to the body-midline, but was different relative to the fixation position. We used a conjunction search task to assess the generality of our previous findings. We found that participants relied on body-centred information and not retinotopic cues. Thus, we provide further evidence that egocentric information, and specifically body-centred information, can persist for several seconds, and that these effects are not specific to either a feature or a conjunction search paradigm.     

Delay improves performance on a haptic spatial matching task

Systematic deviations occur when blindfolded subjects set a test bar parallel to a reference bar in the horizontal plane using haptic information (Kappers and Koenderink 1999, Perception 28:781–795; Kappers 1999, Perception 28:1001–1012). These deviations are assumed to reflect the use of a combination of a biasing egocentric reference frame and an allocentric, more cognitive one (Kappers 2002, Acta Psychol 109:25–40). In two experiments, we have examined the effect of delay between the perception of a reference bar and the parallel setting of a test bar. In both experiments a 10-s delay improved performance. The improvement increased with a larger horizontal (left–right) distance between the bars. This improvement was interpreted as a shift from the egocentric towards the allocentric reference frame during the delay period. Electronic Publication     

Cognitive deficits in preclinical Alzheimer's disease and vascular dementia: patterns of findings from the Kungsholmen Project

Using data from the Kungsholmen Project (KP), we describe a program of research that focuses on preclinical cognitive markers of dementia. A large number of KP studies convincingly demonstrate that there is a preclinical period that spans several years in both Alzheimer's disease (AD) and vascular dementia (VaD), during which cognitive deficits are possible to detect. In AD, the preclinical impairment generalizes across a variety of cognitive domains, including episodic memory, executive functioning, perceptual speed, attention, verbal ability, and visuospatial skill. Although less research has been directed at cognition in preclinical VaD, the emerging evidence suggests a rather broad prodromal impairment in this disease as well. Thus, the nature of the cognitive impairment appears to be largely similar in preclinical AD and VaD. Despite the fact that average group differences in cognitive performance between incident dementia cases and controls are large several years before diagnosis, the distribution of scores in these groups overlap greatly. In order to improve group classification, future research should consider combining cognitive markers with preclinical indicators from other domains (e.g., biological, clinical, social, genetic) into multivariate prediction models.     

Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans

Thirty patients who had undergone either a right or left unilateral temporal lobectomy (14 RTL; 16 LTL) and 16 control participants were tested on a computerized human analogue of the Morris Water Maze. The procedure was designed to compare allocentric and egocentric spatial memory. In the allocentric condition, participants searched for a target location on the screen, guided by object cues. Between trials, participants had to walk around the screen, which disrupted egocentric memory representation. In the egocentric condition, participants remained in the same position, but the object cues were shifted between searches to prevent them from using allocentric memory. Only the RTL group was impaired on the allocentric condition, and neither the LTL nor RTL group was impaired on additional tests of spatial working memory or spatial manipulation. The results support the notion that the right anterior temporal lobe stores long-term allocentric spatial memories.     

The Epidemiology of Dementia Associated with Parkinson's Disease

Parkinson''s disease (PD) is the second most common neurodegenerative illness after Alzheimer''s disease (AD). Cognitive impairment and dementia are common features in PD and characterized by a wide range of cognitive deficits distinct from those seen in AD. Mild cognitive impairment occurs even early in PD and is associated with shorter time to dementia. The purpose of this review is to present recent findings on clinical aspects of dementia in PD and to elucidate underlying clinical and neurobiological risk factors.