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1.
J Alzheimers Dis ; 98(3): 773-792, 2024.
Article in English | MEDLINE | ID: mdl-38461502

ABSTRACT

Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer's disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Cognitive Dysfunction , Dementia , Humans , Aged , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/epidemiology , Risk Factors , Neurocognitive Disorders , Cognitive Dysfunction/epidemiology , Dementia/epidemiology
3.
PLoS One ; 8(4): e60921, 2013.
Article in English | MEDLINE | ID: mdl-23577177

ABSTRACT

Microglial cells closely interact with senile plaques in Alzheimer's disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer's disease, we directly assessed microglial behavior in two mouse models of Alzheimer's disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer's disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aß plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aß vaccination. These data suggest that major microglial functions progressively decline in Alzheimer's disease with the appearance of Aß plaques, and that this functional impairment is reversible by lowering Aß burden, e.g. by means of Aß vaccination.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Microglia/pathology , Plaque, Amyloid/pathology , Protein Multimerization , Amyloid beta-Peptides/genetics , Animals , Cell Movement , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Transgenic , Mutation , Phagocytosis , Protein Structure, Secondary , Spatio-Temporal Analysis
4.
Brain ; 135(Pt 6): 1964-80, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22492561

ABSTRACT

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.


Subject(s)
Infarction, Middle Cerebral Artery/complications , Interleukin-6/metabolism , Neovascularization, Pathologic/etiology , Analysis of Variance , Angiogenic Proteins/genetics , Angiogenic Proteins/metabolism , Animals , Bone Marrow Transplantation/methods , Brain/pathology , Calcium-Binding Proteins/metabolism , Cells, Cultured , Cerebral Cortex/cytology , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Embryo, Mammalian , Endothelial Cells/pathology , Endothelin-1/genetics , Endothelin-1/metabolism , Enzyme-Linked Immunosorbent Assay , Gait Disorders, Neurologic/etiology , Gene Expression Profiling , Gene Expression Regulation/genetics , Glucose/deficiency , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hypoxia/complications , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/physiopathology , Infarction, Middle Cerebral Artery/surgery , Interleukin-6/genetics , Mice , Mice, Knockout/genetics , Microfilament Proteins/metabolism , Neovascularization, Pathologic/metabolism , Neuroglia/physiology , Neurons/drug effects , Oligonucleotide Array Sequence Analysis , Perfusion Imaging , Receptor, trkB/genetics , Receptor, trkB/metabolism , Rotarod Performance Test , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/genetics , Signal Transduction/physiology , Tetrazolium Salts , Thiazoles
5.
Proc Natl Acad Sci U S A ; 106(50): 21407-12, 2009 Dec 15.
Article in English | MEDLINE | ID: mdl-19955445

ABSTRACT

Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-alpha and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.


Subject(s)
Circadian Rhythm/immunology , Inflammation/immunology , Macrophages/immunology , Animals , Gene Expression Regulation , Immunity, Innate , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Lymph Nodes/immunology , Macrophages/metabolism , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Mice , RNA, Messenger/analysis , Spleen/immunology , Tumor Necrosis Factor-alpha/metabolism
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