Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume

Femminella, Grazia Daniela; Dani, Melanie; Wood, Melanie; Fan, Zhen; Calsolaro, Valeria; Atkinson, Rebecca; Edginton, Trudi; Hinz, Rainer; Brooks, David J.; Edison, Paul

doi:10.1212/wnl.0000000000007133

Cited by 80 publications

(60 citation statements)

References 60 publications

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“…conditions preceding the onset of dementia and alphasynucleinopathies, respectively 28,29 . In addition, Femminella et al 30 showed that increased microglial activation as measured with [ 11 C]-PBR28 PET in MCI subjects was associated with higher grey matter and hippocampal volume, suggesting that neuroinflammation is again involved in early stages of the disease or may even play a protective role in the disease trajectory.…”

Section: Discussionmentioning

confidence: 99%

Correlation of Microglial Activation with White Matter Changes in Dementia with Lewy Bodies

Nicastro

Mak

Williams

et al. 2019

Preprint

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Dementia with Lewy bodies (DLB) is the second-leading degenerative dementia afterAlzheimer's disase. Neuropathologically, it is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer pathology. Neuroinflammation is increasingly recognized as a significant contributor of degeneration. Objective: to examine the relationship between microglial activation as measured with [ 11 C]-PK11195 brain PET and MR diffusion tensor imaging (DTI) in DLB. Methods: nineteen clinically probable DLB and 20 similarly aged controls underwent structural MRI with T1-weighted and 3T DTI sequences. Eighteen DLB subjects also underwent [ 11 C]-PK11195 PET imaging. Tract-Based Spatial Statistics (TBSS) were performed to compare DTI parameters in DLB relative to controls and identify associations of [ 11 C]-PK11195 binding with white matter integrity. Results: TBSS showed widespread changes in all DTI parameters in the DLB group compared to controls (Threshold Free Cluster Enhancement (TFCE) p < 0.05). [ 11 C]-PK11195 binding in parietal cortices also correlated with widespread lower mean and radial diffusivity (TFCE p < 0.05). Conclusion:Our study demonstrates that higher PK11195 binding is associated with a relative preservation of white matter, positioning neuroinflammation as a potential early marker in the DLB pathogenic cascade.

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Section: Discussionmentioning

confidence: 99%

Correlation of Microglial Activation with White Matter Changes in Dementia with Lewy Bodies

Nicastro

Mak

Williams

et al. 2019

Preprint

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“…In addition to the two classic diagnostic hallmarks of AD, Aβ plaques and neurofibrillary tangles, the brain of patients with AD exhibits evidence of a sustained inflammatory response ( Mandrekar and Landreth, 2010 ; Femminella et al, 2018 , 2019 ). In the acute phase, inflammation in the brain represents an established defense against infections, toxins, and injury.…”

Section: Neuroinflammation In the Pathogenesis Of Alzheimer’s Diseasementioning

confidence: 99%

Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease

et al. 2020

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Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population, representing a global public health priority. Despite a large improvement in understanding the pathogenesis of AD, the etiology of this disorder remains still unclear, and no current treatment is able to prevent, slow, or stop its progression. Thus, there is a keen interest in the identification and modification of the risk factors and novel molecular mechanisms associated with the development and progression of AD. In this context, it is worth noting that several findings support the existence of a direct link between neuronal and non-neuronal inflammation/infection and AD progression. Importantly, recent studies are now supporting the existence of a direct relationship between periodontitis, a chronic inflammatory oral disease, and AD. The mechanisms underlying the association remain to be fully elucidated, however, it is generally accepted, although not confirmed, that oral pathogens can penetrate the bloodstream, inducing a low-grade systemic inflammation that negatively affects brain function. Indeed, a recent report demonstrated that oral pathogens and their toxic proteins infect the brain of AD patients. For instance, when AD progresses from the early to the more advanced stages, patients could no longer be able to adequately adhere to proper oral hygiene practices, thus leading to oral dysbiosis that, in turn, fuels infection, such as periodontitis. Therefore, in this review, we will provide an update on the emerging (preclinical and clinical) evidence that supports the relationship existing between periodontitis and AD. More in detail, we will discuss data attesting that periodontitis and AD share common risk factors and a similar hyper-inflammatory phenotype.

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“…However, a long-standing pro-inflammatory and pro-oxidant environment sustained by persistent microglia activation is detrimental as it may contribute to neurodegeneration. This is particularly relevant in the context of Alzheimer's (AD) and Parkinson's disease (PD) [7,8]. Metabolic changes in microglia have also been associated with a state of chronic low-grade inflammation observed during aging (i.e., inflamm-aging) [9,10].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

et al. 2020

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Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

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Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume

Cited by 80 publications

References 60 publications

Correlation of Microglial Activation with White Matter Changes in Dementia with Lewy Bodies

Correlation of Microglial Activation with White Matter Changes in Dementia with Lewy Bodies

Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

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