Rule induction performance in amnestic mild cognitive impairment and Alzheimer’s dementia: examining the role of simple and biconditional rule learning processes

Introduction: Rule induction tests such as the Wisconsin Card Sorting Test require executive control processes, but also the learning and memorization of simple stimulus–response rules. In this study, we examined the contribution of diminished learning and memorization of simple rules to complex rule induction test performance in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer’s dementia (AD). Method: Twenty-six aMCI patients, 39 AD patients, and 32 control participants were included. A task was used in which the memory load and the complexity of the rules were independently manipulated. This task consisted of three conditions: a simple two-rule learning condition (Condition 1), a simple four-rule learning condition (inducing an increase in memory load, Condition 2), and a complex biconditional four-rule learning condition—inducing an increase in complexity and, hence, executive control load (Condition 3). Results: Performance of AD patients declined disproportionately when the number of simple rules that had to be memorized increased (from Condition 1 to 2). An additional increment in complexity (from Condition 2 to 3) did not, however, disproportionately affect performance of the patients. Performance of the aMCI patients did not differ from that of the control participants. In the patient group, correlation analysis showed that memory performance correlated with Condition 1 performance, whereas executive task performance correlated with Condition 2 performance. Conclusions: These results indicate that the reduced learning and memorization of underlying task rules explains a significant part of the diminished complex rule induction performance commonly reported in AD, although results from the correlation analysis suggest involvement of executive control functions as well. Taken together, these findings suggest that care is needed when interpreting rule induction task performance in terms of executive function deficits in these patients

Occurrence and phenomenology of hallucinations in the general population: A large online survey

Although epidemiological studies report that hallucinations occur in 6–15% of the general population, little is known about their phenomenology. To overcome this paucity, this study investigates the phenomenological characteristics of hallucinations in the general population, by using a nationally promoted online survey to assess hallucination phenomenology in four sensory modalities, through a self-report version of the Questionnaire for Psychotic Experiences (QPE), in 10,448 participants (aged 14–88 years). The phenomenology of hallucinations was assessed if hallucinations reportedly occurred in the past month. In the past month, auditory hallucinations were reported most frequently (29.5%), followed by visual (21.5%), tactile (19.9%), and olfactory hallucinations (17.3%); hallucinations in two or more modalities were reported by 47.6%. Substantial numbers of participants rated their hallucinations as severe, due to negative content (16.0–31.6%), previous bothersome experiences (14.8–20.2%), ensuing distress (10.5–16.8%), and/or ensuing disfunctioning (12.7–17.3%). Decreased insight was found in 10.2–11.4%. Hypnagogia was reported by 9.0–10.6%, and bereavement hallucinations by 2.8%. Despite a low prevalence of delusions (7.0%), these phenomena were significantly associated with recent hallucinations, observed in up to 13.4% of the participants with hallucinations during the past week (p < 0.001). Our results indicate a wide variety of the phenomenology of hallucinations in the general population and support the existence of a phenomenological continuum.publishedVersio

The Global ECT-MRI Research Collaboration (GEMRIC): Establishing a multi-site investigation of the neural mechanisms underlying response to electroconvulsive therapy.

Major depression, currently the world's primary cause of disability, leads to profound personal suffering and increased risk of suicide. Unfortunately, the success of antidepressant treatment varies amongst individuals and can take weeks to months in those who respond. Electroconvulsive therapy (ECT), generally prescribed for the most severely depressed and when standard treatments fail, produces a more rapid response and remains the most effective intervention for severe depression. Exploring the neurobiological effects of ECT is thus an ideal approach to better understand the mechanisms of successful therapeutic response. Though several recent neuroimaging studies show structural and functional changes associated with ECT, not all brain changes associate with clinical outcome. Larger studies that can address individual differences in clinical and treatment parameters may better target biological factors relating to or predictive of ECT-related therapeutic response. We have thus formed the Global ECT-MRI Research Collaboration (GEMRIC) that aims to combine longitudinal neuroimaging as well as clinical, behavioral and other physiological data across multiple independent sites. Here, we summarize the ECT sample characteristics from currently participating sites, and the common data-repository and standardized image analysis pipeline developed for this initiative. This includes data harmonization across sites and MRI platforms, and a method for obtaining unbiased estimates of structural change based on longitudinal measurements with serial MRI scans. The optimized analysis pipeline, together with the large and heterogeneous combined GEMRIC dataset, will provide new opportunities to elucidate the mechanisms of ECT response and the factors mediating and predictive of clinical outcomes, which may ultimately lead to more effective personalized treatment approaches

Genetic plasticity of the Shigella virulence plasmid is mediated by intra- and inter-molecular events between insertion sequences

Acquisition of a single copy, large virulence plasmid, pINV, led to the emergence of Shigella spp. from Escherichia coli. The plasmid encodes a Type III secretion system (T3SS) on a 30kb pathogenicity island (PAI), and is maintained in a bacterial population through a series of toxin:antitoxin (TA) systems which mediate post-segrega tional killing (PSK). The T3SS imposes a significant cost on the bacterium, and strains which have lost the plasmid and/or genes encoding the T3SS grow faster than wild-type strains in the laboratory, and fail to bind the indicator dye Congo Red (CR). Our aim was to define the molecular events in Shigella flexneri that cause loss of Type III secretion (T3S), and to examine whether TA systems exert positional effects on pINV. During growth at 37°C, we found that deletions of regions of the plasmid including the PAI lead to the emergence of CR-negative colonies; deletions occur through intra-molecula r recombination events between insertion sequences (ISs) flanking the PAI. Furthermore, by repositioning MvpAT (which belongs to the VapBC family of TA systems) near the PAI, we demonstrate that the location of this TA system alters the rearrangements that lead to loss of T3S, indicating that MvpAT acts both globally (by reducing loss of pINV through PSK) as well as locally (by preventing loss of adjacent sequences). During growth at environmental temperatures, we show for the first time that pINV spontaneously integrates into different sites in the chromosome, and this is mediated by inter-molecular events involving IS 1294. Integration leads to reduced PAI gene expression and impaired secretion through the T3SS, while excision of pINV from the chromosome restores T3SS function. Therefore, pINV integration provides a reversible mechanism for Shigella to circumvent the metabolic burden imposed by pINV. Intra- and inter-molecular events between ISs, which are abundant in Shigella spp., mediate plasticity of S. flexneri pINV

Cognitive functioning and microvascular disease

Cognitive impairment and dementia form a major health issue, affecting a considerable proportion of the aging population. Cerebral vascular damage is increasingly recognized as one of the main causes of cognitive decline in aging and dementia. Another main cause of cognitive deterioration in older people are neurodegenerative processes, resulting in Alzheimer’s disease (AD) type pathologies. Evidence is growing for a crucial role of vascular damage in AD. A current challenge is to explore the role of vascular disease in causing cognitive impairment, by itself or in interaction with AD. Besides the cerebral large vessels, the cerebral microvasculature is fundamentally important for brain functioning. Microvascular damage is important for the entire range of cognitive functioning, from subtle decrements in normal aging to frank dementia. The research in this thesis aimed to investigate the relation between biomarkers of microvascular disease and cognitive functioning. In the first part of this thesis, we investigated measures of microvascular disease in parts of the body outside the brain and the relation with cognitive functioning. We show in that retinal microvascular changes, microalbuminuria, and low-grade inflammation and endothelial dysfunction were related to subtle cognitive decrements in non-demented older individuals. Despite consistency of the findings, in all studies associations between markers of microvascular disease and cognitive functioning were rather weak. Thus, these biomarkers of systemic microvascular disease are of limited value as markers of reduced cognitive performance in the population. In the second part of this thesis, measures of microvascular disease in the brain were investigated, in patients with amnestic mild cognitive impairment (aMCI) or early AD. Multiple microbleeds were associated with disruptions of the microstructure and organization of the cerebral network as measured with diffusion tensor imaging (DTI), independent of other measures of small vessel disease or atrophy. We used 7 Tesla MRI to investigate the presence of microbleeds in detail and to image cortical microinfarcts. We showed that the majority of patients with aMCI or early AD exhibit cerebral microbleeds. Microinfarct numbers were not significantly increased in patients relative to controls. They did appear to be related to cerebral microbleed numbers and to other, larger, cortical infarcts. We showed that cerebral microvascular lesions are associated with (end-stage) dementia presence, but not so much with cognitive functioning in patients with AD. In the third part of this thesis, we investigated spatial navigation, a cognitive function that is often affected in patients with aMCI or early AD, which has high clinical relevance. On three fundamental aspects of spatial navigation, patients performed worse than controls, and patients with aMCI were at an intermediate level between controls and patients with AD. In conclusion, microvascular disease is important for cognition. A consistent, but rather weak, association between markers of microvascular disease and cognitive functioning is present in people without cognitive complaints. In patients with aMCI or early AD, cerebral markers of microvascular disease are prevalent and are related to other vascular brain damage. Our findings contribute to a better understanding of vascular-related cognitive impairment

Associations between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities: a systematic review

Retinal microvascular changes can be visualized noninvasively and have been associated with cognitive decline and brain changes in relation to aging and vascular disease. We systematically reviewed studies, published between 1990 and November 2012, on the association between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities, in the context of aging and vascular risk factors. In cross-sectional studies (k=26), retinal microvascular changes were associated with the presence of dementia (range of odds ratios (ORs) 1.17;5.57), with modest decrements in cognitive functioning in nondemented people (effect sizes -0.25;0.03), and with brain imaging abnormalities, including atrophy and vascular lesions (ORs 0.94;2.95). Longitudinal studies were more sparse (k=9) and showed no consistent associations between retinal microvascular changes and dementia or cognitive dysfunctioning 3 to 15 years later (ORs and hazard ratios 0.77;1.55). However, there were indications of prospective associations with brain imaging abnormalities ((ORs) 0.81;3.19). In conclusion, particularly in cross-sectional studies there is a correlation between retinal microvascular changes and dementia, cognitive impairment, and brain imaging abnormalities. Associations are strongest for more severe retinal microvascular abnormalities. Retinal microvascular abnormalities may offer an important window on the brain for etiological studies

Rule induction performance in amnestic mild cognitive impairment and Alzheimer's dementia: Examining the role of simple and biconditional rule learning processes

INTRODUCTION: Rule induction tests such as the Wisconsin Card Sorting Test require executive control processes, but also the learning and memorization of simple stimulus-response rules. In this study, we examined the contribution of diminished learning and memorization of simple rules to complex rule induction test performance in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's dementia (AD). METHOD: Twenty-six aMCI patients, 39 AD patients, and 32 control participants were included. A task was used in which the memory load and the complexity of the rules were independently manipulated. This task consisted of three conditions: a simple two-rule learning condition (Condition 1), a simple four-rule learning condition (inducing an increase in memory load, Condition 2), and a complex biconditional four-rule learning condition-inducing an increase in complexity and, hence, executive control load (Condition 3). RESULTS: Performance of AD patients declined disproportionately when the number of simple rules that had to be memorized increased (from Condition 1 to 2). An additional increment in complexity (from Condition 2 to 3) did not, however, disproportionately affect performance of the patients. Performance of the aMCI patients did not differ from that of the control participants. In the patient group, correlation analysis showed that memory performance correlated with Condition 1 performance, whereas executive task performance correlated with Condition 2 performance. CONCLUSIONS: These results indicate that the reduced learning and memorization of underlying task rules explains a significant part of the diminished complex rule induction performance commonly reported in AD, although results from the correlation analysis suggest involvement of executive control functions as well. Taken together, these findings suggest that care is needed when interpreting rule induction task performance in terms of executive function deficits in these patients

Working memory binding and episodic memory formation in aging, mild cognitive impairment, and Alzheimer's dementia

INTRODUCTION: Recent studies indicate that in both normal and pathological aging working memory (WM) performance deteriorates, especially when associations have to be maintained. However, most studies typically do not assess the relationship between WM and episodic memory formation. In the present study, we examined WM and episodic memory formation in normal aging and in patients with early Alzheimer's disease (mild cognitive impairment, MCI; and Alzheimer's dementia, AD). METHOD: In the first study, 26 young adults (mean age 29.6 years) were compared to 18 middle-aged adults (mean age 52.2 years) and 25 older adults (mean age 72.8 years). We used an associative delayed-match-to-sample WM task, which requires participants to maintain two pairs of faces and houses presented on a computer screen for short (3 s) or long (6 s) maintenance intervals. After the WM task, an unexpected subsequent associative memory task was administered (two-alternative forced choice). In the second study, 27 patients with AD and 19 patients with MCI were compared to 25 older controls, using the same paradigm as that in Experiment 1. RESULTS: Older adults performed worse than both middle-aged and young adults. No effect of delay was observed in the healthy adults, and pairs that were processed during long maintenance intervals were not better remembered in the subsequent memory task. In the MCI and AD patients, longer maintenance intervals hampered the task performance. Also, both patient groups performed significantly worse than controls on the episodic memory task as well as the associative WM task. CONCLUSIONS: Aging and AD present with a decline in WM binding, a finding that extends similar results in episodic memory. Longer delays in the WM task did not affect episodic memory formation. We conclude that WM deficits are found when WM capacity is exceeded, which may occur during associative processing

Working memory binding and episodic memory formation in aging, mild cognitive impairment, and Alzheimer's dementia

Item does not contain fulltextINTRODUCTION: Recent studies indicate that in both normal and pathological aging working memory (WM) performance deteriorates, especially when associations have to be maintained. However, most studies typically do not assess the relationship between WM and episodic memory formation. In the present study, we examined WM and episodic memory formation in normal aging and in patients with early Alzheimer's disease (mild cognitive impairment, MCI; and Alzheimer's dementia, AD). METHOD: In the first study, 26 young adults (mean age 29.6 years) were compared to 18 middle-aged adults (mean age 52.2 years) and 25 older adults (mean age 72.8 years). We used an associative delayed-match-to-sample WM task, which requires participants to maintain two pairs of faces and houses presented on a computer screen for short (3 s) or long (6 s) maintenance intervals. After the WM task, an unexpected subsequent associative memory task was administered (two-alternative forced choice). In the second study, 27 patients with AD and 19 patients with MCI were compared to 25 older controls, using the same paradigm as that in Experiment 1. RESULTS: Older adults performed worse than both middle-aged and young adults. No effect of delay was observed in the healthy adults, and pairs that were processed during long maintenance intervals were not better remembered in the subsequent memory task. In the MCI and AD patients, longer maintenance intervals hampered the task performance. Also, both patient groups performed significantly worse than controls on the episodic memory task as well as the associative WM task. CONCLUSIONS: Aging and AD present with a decline in WM binding, a finding that extends similar results in episodic memory. Longer delays in the WM task did not affect episodic memory formation. We conclude that WM deficits are found when WM capacity is exceeded, which may occur during associative processing

Vascular retinopathy in relation to cognitive functioning in an older population--the Hoorn Study

To the Editor: Cognitive impairment and dementia are important health problems that may be caused by vascular damage in the brain.[1] The cerebral vasculature is anatomically, embryologically, and physiologically related to that of the retina, and both are sensitive to exposure to vascular risk factors.[2, 3] Vascular damage to the retina is easy to measure noninvasively. Hence, visualization of retinal vessels may offer insight into the status of the vessels in the brain and thus provide insight into vascular causes of late-life cognitive impairment. A recent systematic review found variable associations between retinal vascular changes and performance on various cognitive domains in persons without dementia.[4, 5] The goal of the current study was to extend these findings by assessing these associations in a population-based cohort using a detailed neuropsychological examination