Assessment of microglial activation in mild cognitive impairment using [11C](R)-PK11195 and PET

Abstract Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer’s disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia.

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CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

10.1101/687269 ◽

2019 ◽

Author(s):

Edward N. Wilson ◽

Michelle S. Swarovski ◽

Patricia Linortner ◽

Marian Shahid ◽

Abigail J. Zuckerman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Microglial Activation ◽

Soluble Form ◽

Motor Symptoms ◽

Cognitively Normal ◽

Csf Concentration

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD

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Microglial activation and amyloid deposition in mild cognitive impairment: A PET study

Neurology ◽

10.1212/01.wnl.0000338622.27876.0d ◽

2009 ◽

Vol 72 (1) ◽

pp. 56-62 ◽

Cited By ~ 196

Author(s):

A. Okello ◽

P. Edison ◽

H. A. Archer ◽

F. E. Turkheimer ◽

J. Kennedy ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Microglial Activation ◽

Amyloid Deposition

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Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17741395 ◽

2017 ◽

Vol 38 (11) ◽

pp. 1885-1895 ◽

Cited By ~ 11

Author(s):

Dunja Knezevic ◽

Nicolaas Paul LG Verhoeff ◽

Sina Hafizi ◽

Antonio P Strafella ◽

Ariel Graff-Guerrero ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Healthy Volunteers ◽

Microglial Activation ◽

Standardized Uptake Value ◽

Compartment Model ◽

Input Function ◽

Amnestic Mild Cognitive Impairment ◽

Transitional State

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer’s disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aβ) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [18F]-FEPPA and [11C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [18F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [11C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [11C]-PIB binding in the cortical regions. No significant differences in [18F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [18F]-FEPPA and [11C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aβ burden is evident in the aMCI stage, microglial activation may not be present.

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P4-325: RELATIONSHIP BETWEEN MICROGLIAL ACTIVATION MEASURED BY FLUTRICICLAMIDE AND MICROSTRUCTURAL ALTERATION IN ALZHEIMER'S DISEASE AND MILD COGNITIVE IMPAIRMENT SUBJECTS

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3995 ◽

2019 ◽

Vol 15 ◽

pp. P1419-P1420

Author(s):

Valeria Calsolaro ◽

Adam Hampshire ◽

Grazia Daniela Femminella ◽

David J. Brooks ◽

Paul Edison

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Microglial Activation

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In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323894 ◽

2020 ◽

Vol 92 (1) ◽

pp. 45-52

Author(s):

Audrey Low ◽

Elijah Mak ◽

Maura Malpetti ◽

Luca Passamonti ◽

Nicolas Nicastro ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Pet Imaging ◽

Microglial Activation ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Dominance Analysis ◽

Vessel Disease

IntroductionAssociations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging.MethodsForty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer’s disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195.ResultsGlobal [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=<0.001–0.002) and orbitofrontal cortex (β=0.51–0.57, t=3.53–4.30, pFDR=0.001–0.004).ConclusionMicroglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

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