Association of neuroinflammation with episodic memory: a [11C]PBR28 PET study in cognitively discordant twin pairs

Abstract

Alzheimer’s disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer’s disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer’s disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72–77 years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014–17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer’s disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05–0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer’s disease process.

Imaging Neuroinflammation in Neurodegenerative Disorders

“…The localization of inflammation matched the clinical syndrome (37) and correlated negatively with metabolism measured with 18 F-FDG PET (35)(36)(37). Furthermore, the degree of TSPO uptake correlated with worse cognition (33,38,39), better than the degree of amyloid deposition and, together with the degree of tau deposition, predicted the degree of cognitive worsening over 3 y (40). Inflammation correlated with white matter changes (41) and impaired large-scale functional connectivity on MRI (42).…”

Co-twin design in brain imaging—review on biomarkers of Alzheimer's disease

“…Of course, it is not possible to draw conclusions from a case study of 1 twin pair, but interestingly, subsequent studies in cognitively discordant twin pairs from the older FTC study have confirmed lower glucose metabolism and smaller hippocampal volumes in co-twins with cognitive impairment compared with their co-twins without cognitive impairment ( Järvenpää et al 2004 ; Virta et al 2009 ). Notably, also an association between neuroinflammation and cognition has been found in cognitively discordant twin pairs ( Lindgren et al 2020 ).…”

“…Two studies in Finnish twins have further looked at twin pairs discordant for episodic memory in relation to PET tracers measuring neuroinflammation ( Lindgren et al 2020 ) and amyloid pathology ( Lindgren et al 2021 ). These studies can inform if the associations between clinical and biological characteristics of AD are evident when controlling for shared genetic influences or alternatively implicate that these associations are mediated by genetic effects.…”

“…These studies can inform if the associations between clinical and biological characteristics of AD are evident when controlling for shared genetic influences or alternatively implicate that these associations are mediated by genetic effects. In 10 twin pairs, co-twins with poorer episodic memory had about 20% higher cortical neuroinflammation in AD vulnerable regions compared with their co-twins with better episodic memory ( Lindgren et al 2020 ). A study including 45 twin pairs indicated that within-twin pair differences in cortical amyloid pathology were significantly related to within-twin pair differences in episodic memory: co-twins with poorer episodic memory had greater amyloid-β levels than their co-twins with better episodic memory ( Lindgren et al 2021 ).…”

Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures

“…The glial role in the innate immune system also involves general ‘sickness’ symptoms that shift an organism’s behavior to preserve energy at a time of high energy demand (Dantzer & Kelley, 2007; VanElzakker et al, 2019). However, long-term glial activation can disrupt the delicate symbiosis of glia, blood vessels, neurons, and cerebrospinal fluid in normal central nervous system function, and ongoing glial activation occurs in multiple neurological and neuropsychiatric conditions (VanElzakker et al, 2019) and is associated with symptoms that are commonly reported in PASC such as disrupted cognition (Barrientos et al, 2006; Lindgren et al, 2020), increased pain (Loggia et al, 2015), and other nonspecific symptoms of sickness.…”