Physostigmine results in an increased decrement in brain glucose consumption in Alzheimer's disease

Blin, J.; Ivanoiu, Adrian; Volder, Anne De; Michel, Christian; Bol, Anne; Dumoulin, Christine; Serón, Xavier; Duprez, Thierry; Laterre, Emile-Christian

doi:10.1007/s002130050564

Cited by 10 publications

(3 citation statements)

References 39 publications

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“…Furthermore, similar to our findings in the 3xTgAD mouse, anticholinesterase treatment improved attention in MCI and AD patients (Sahakian et al, 1993ab; Lawrence & Sahakian, 1995; Blin et al, 1998; Rockwood et al, 2004; Foldi et al, 2005a, Bentley et al, 2008), interestingly without significantly affecting learning abilities (Sahakian et al, 1993ab). However, it remains to be investigated whether attentional impairments in 3xTGAD mice and AD patients are indeed comparable and based on the same pathological processes.…”

Section: Discussionsupporting

confidence: 89%

Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)

Romberg¹,

et al. 2011

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Several mouse models of Alzheimer’s Disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V and tauP301L mutations) and wild type control mice on a newly-developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects; first, although 3xTgAD mice initially responded as accurately as wild type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.

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Section: Discussionsupporting

confidence: 89%

Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)

Romberg¹,

et al. 2011

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“…Furthermore, whereas the memory impairments in AD seem to derive largely from selective atrophy of medial temporal structures (Fox et al, 2001), the attentional defects of AD most likely reflect a deficiency of input – both cortico-cortical and cholinergic – to areas that are relatively intact structurally (Perry & Hodges, 1999). This seems consistent with observations that cholinesterase inhibitors can improve attention more than memory scores in AD (Lawrence & Sahakian, 1995; Sahakian et al, 1993; Sahakian, 1988; Sahakian et al, 1987; Blin et al, 1998; Foldi et al, 2005); and that lesions to basal forebrain cholinergic neurons can induce deficits in visual-attention more than memory tasks (Everitt & Robbins, 1997; Kirkby & Higgins, 1998) that may be reversed with cholinesterase inhibition (Balducci et al, 2003). One of the principal aims of our study was to test whether AD-associated impairments in attention, at the levels of both behavioural manifestations and fMRI activations, are cholinergic dependent.…”

Section: Discussionsupporting

confidence: 88%

Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health

Bentley

Driver

Dolan

2008

Brain

106

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Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate that physostigmine can improve both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions in AD, while perturbing the normal pattern of responses in many of the same regions in healthy controls.

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“…[ 18 F]Setoperone has been used by a number of investigators to study cortical 5-HT 2A receptor levels in depression, 49;50 schizophrenia, 51;52 and Alzheimer’s disease, 53 and to measure the effects of antipsychotic and antidepressant medications 54;55 on 5-HT 2A receptor levels. [ 18 F]setoperone binding to 5-HT 2 receptors in cortex largely reflects 5-HT 2A receptors, having an affinity for 5-HT 2A versus 5-HT 2C receptors of 100:1.…”

Section: Methodsmentioning

confidence: 99%

Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

Iorio

Watkins²,

Dietrich³

et al. 2012

Arch Gen Psychiatry

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Context MDMA (ecstasy) is a popular recreational drug that produces loss of serotonin (5-HT) axons in animal models. Whether MDMA produces chronic reductions in 5-HT signaling in humans remains controversial. Objective To determine if MDMA use is associated with chronic reductions in serotonin signaling in female human cerebral cortex as reflected by increased 5-HT2A receptors. Design Cross sectional case-control study comparing 5-HT2A receptor levels in abstinent female MDMA polydrug users to MDMA-naive females; within-group design assessing the association of lifetime MDMA use and 5-HT2A receptors. Subjects had at least 90 days abstinence from MDMA use as verified by hair sampling. Cortical 5-HT2A receptor levels were assayed with the 5HT2A-specific Positron Emission Tomography (PET) radioligand [18F]setoperone. Setting Academic Medical Center Research Laboratory. Participants Volunteer female MDMA users (N=14) and MDMA-naive controls (N=10). Main exclusion criteria were non-drug-related DSM-IV axis I psychiatric disorders and general medical illness. Main Outcome Measure Cortical 5-HT2A receptor non-displaceable binding potential (5-HT2ABPND). Results MDMA users had increased 5-HT2ABPND in occipital-parietal (19.7%), temporal (20.5%), occipito-temporal-parietal (18.3%), frontal (16.6%), and fronto-parietal (18.5%) regions (p<0.05; corrected). Lifetime MDMA use associated positively with 5-HT2ABPND in fronto-parietal (β=0.665;p=0.007), occipito-temporal (β=0.798;p=0.002), fronto-limbic (β=0.634;p=0.024), and frontal (β=0.691;p=0.008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on 5-HT2ABPND. Conclusions Human recreational MDMA use is associated with long-lasting increases in 5-HT2A receptor density. 5-HT2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA produces chronic 5-HT neurotoxicity in humans. Given the broad role of 5-HT in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

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Physostigmine results in an increased decrement in brain glucose consumption in Alzheimer's disease

Cited by 10 publications

References 39 publications

Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)

Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)

Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health

Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

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