Hypermetabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation

Apostolova, Ivayla; Lange, Catharina; Mäurer, Anja; Suppa, Per; Spies, Lothar; Grothe, Michel J.; Nierhaus, Till; Fiebach, Jochen B.; Steinhagen‐Thiessen, Elisabeth; Buchert, Ralph; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neurobiolaging.2018.01.002

Cited by 26 publications

(27 citation statements)

References 59 publications

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“…Our results of cerebral glucose hypermetabolism observed in the 5M+2M (galactose-untreated) Tg2576 mice are in line with the similar report on FDG-PET assessment in the presymptomatic-staged Tg2576 mice model, where it was proposed to reflect a neuronal compensatory mechanism (Luo et al, 2012). Indeed, in patients with mild cognitive impairment or mild dementia glucose metabolism in the hippocampus was increased and negatively correlated with the performance in several cognitive subdomains (Apostolova et al, 2018). Luo and co-workers (Luo et al, 2012), showed that cerebral glucose hypermetabolism in this particular transgenic fAD model decreases with age, which has been evidenced in average reductions in the cortical region being -17.7% in 10M+2M (galactose-untreated) Tg2576 mice in our work and -20% in >18 month-old Tg2576 mice in the research of others (Coleman et al, 2017).…”

Section: Msupporting

confidence: 91%

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

et al. 2019

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Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5-(5M) and 10-(10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid ß1-42 (sAß1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAß1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

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Section: Msupporting

confidence: 91%

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

et al. 2019

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“…In contrast, such positive correlation was not confirmed in a recent study enrolling a heterogeneous population of cognitively impaired patients. In this case, hippocampal hypermetabolism was interpreted as a maladaptive, detrimental event, rather than a beneficial compensatory response . Results obtained in animal models appear in line with clinical data, as a peak in brain metabolic rate was described in Tg2576 AD mice at 7 months of age, progressively decreasing to reach wild type levels by 19 months of age .…”

Section: Brain Metabolic Activitysupporting

confidence: 71%

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

2018

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Alzheimer's disease (AD) is characterized by extensive neurodegeneration and inflammation in selective brain areas, linked to severely disabling cognitive deficits. Before full manifestation, different stages appear with progressively increased brain pathology and cognitive impairment. This significantly extends the time lag between initial molecular triggers and appearance of detectable symptoms. Notably, a number of studies in the last decade have revealed that in the early stage of mild cognitive impairment, events that appear in contrast with neuronal distress may occur. These have been reproduced in vitro and in animal models and include increase in synaptic elements, increase in synaptic and metabolic activity, enhancement of neurotrophic milieu and changes in glial cell reactivity and inflammation. They have been interpreted as compensatory responses that could either delay disease progression or, in the long run, result detrimental. For this reason, these mechanisms define a new and previously undervalued window of opportunity for intervention. Their importance resides especially in their early appearance. Directing efforts to better characterize this stage, in order to identify new pharmacological targets, is an exciting new avenue to future advances in AD research.

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“…We hypothesize that the identified bio-neural mode might represent a promising innovative composite biomarker to track in vivo the dynamic interplay between molecular mechanisms and network organizational patterns related to AD pathophysiology. The present study involved individuals at risk of developing AD and, thus, may support the hypothesis of strong interindividual variability in adaptive responses and compensatory mechanisms ensuring brain and body homeostasis 3,[33][34][35][36] . Longterm follow-up studies, including a sufficient number of progressors to symptomatic stages, are necessary to clarify whether the bio-neural mode may correspond to adaptive/compensatory dynamics.…”

Section: Discussionsupporting

confidence: 77%

Association of brain network dynamics with plasma biomarkers in subjective memory complainers

Chiesa

Houot²,

Vergallo³

et al. 2020

Neurobiology of Aging

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Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at risk for Alzheimer's disease. In 205 subjective memory complainers (124 females, mean age: 75.7 ± 3.4), individual functional connectome was computed for a total of 3081 functional connections (set A) and 6 core plasma biomarkers of Alzheimer's disease (set B) were assessed. Partial least squares correlation analysis identified one dimension of population covariation between the 2 sets (p < 0.006), which we named bioneural mode.Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend toward significance (bootstrap resampling = 1.64). The salience, the language, the visuospatial, and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bioneural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.

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Hypermetabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation

Cited by 26 publications

References 59 publications

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

Association of brain network dynamics with plasma biomarkers in subjective memory complainers

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