Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment

Zou, James; Tao, Sha; Johnson, Aubrey S.; Tomljanovic, Zeljko; Polly, Krista; Klein, Julia; Razlighi, Qolamreza R.; Brickman, Adam M.; Lee, Seonjoo; Stern, Yaakov; Kreisl, William Charles

doi:10.1016/j.neurobiolaging.2019.09.019

Cited by 46 publications

(57 citation statements)

References 50 publications

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“…Zou et al. showed that microglial activation assessed by [ 11 C]PBR28 is independently associated with amyloid load and memory impairment, but not with tau burden assessed by [ 18 F]florbetaben and [ 18 F]MK-6240, respectively, in patients with AD ( 74 ). Whereas Dani et al showed that [ 11 C]PBR28-measured microglial activation correlates with both tau and Aβ deposition assessed by [ 18 F]flortaucipir and [ 18 F]flutemetamol in patients with AD ( 69 ) ( Figures 2D, E ).…”

Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

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Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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“…20,21 Although AIF-free methods inherently introduce bias, several such studies have detected increased TSPO in various neurological disorders, with colocalization to abnormalities in other biomarkers. 22,23 In addition, AIF-free methods often reduce variance caused by inter-subject differences in physiological TSPO expression, thus improving power for statistical analysis. 21 Because binding behavior may differ among different radioligands and diseases, we recommend validating pseudo-reference methods against arterial sampling prior to their application.…”

Section: Overcoming Obstacles To Identifying Neuroinflammation Using Pet Imagingmentioning

confidence: 99%

“…49,50 The exact pathological stimulus for increased TSPO in AD remains unclear. Studies have observed increased TSPO binding in asymptomatic individuals with incidental amyloid positivity 23,51 and in participants meeting clinical criteria for amnestic MCI or mild AD with absence of amyloid binding on PET. 23,52 This suggests that TSPO may increase in response to both amyloid deposition and amyloid-independent neurodegeneration.…”

Section: Neurodegenerative Disorders 41 Alzheimer's Disease (Ad)mentioning

confidence: 99%

PET imaging of neuroinflammation in neurological disorders

Kreisl

Kim

Coughlin³

et al. 2020

The Lancet Neurology

140

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“…Our current study selected a subset participants from a pre-established research cohort. In a prior study of the larger cohort, both 18 F-MK-6240 and 11 C-PBR28 binding were greater in amyloid-positive than in amyloid-negative participants, specifically in neocortical regions for 11 C-PBR28 and in the medial temporal lobe for 18 F-MK-6240 [35]. In our sub-sample, we observed similar regional patterns of increased 11 C-PBR28 and 18 F-MK-6240 binding in association with lower UPSIT scores, suggesting that odor identification impairment may be mechanistically linked to inflammation and tau pathology, and not just a nonspecific measure of neurodegeneration.…”

Section: Discussionmentioning

confidence: 98%

Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease

Klein

Yan

Johnson

et al. 2020

Preprint

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Background: Olfactory impairment is evident in Alzheimers disease (AD), however, its precise relationships with in vivo measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET and fifty-three underwent 11C-PBR28 PET to measure tau pathology and neuroinflammation, respectively. Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau) and beta;-amyloid (AB42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). Conclusions: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. That amyloid-positivity and cognitive impairment are independently associated with odor identification suggests that low UPSIT performance may signify risk of AD pathophysiology in cognitively normal individuals and that impaired odor identification is associated with AD and non-AD-related neurodegeneration.

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Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment

Cited by 46 publications

References 50 publications

PET Imaging of Neuroinflammation in Alzheimer’s Disease

PET Imaging of Neuroinflammation in Alzheimer’s Disease

PET imaging of neuroinflammation in neurological disorders

Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease

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