Regional brain shrinkage over two years: Individual differences and effects of pro-inflammatory genetic polymorphisms

Abstract

We examined regional changes in brain volume in healthy adults (N = 167, age 19-79 years at baseline; N = 90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (HC), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the HC, CbH, In, OF, and the PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants mediated shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1βC-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFRC677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan.

Age and sex related differences in subcortical brain iron concentrations among healthy adults

“…Inflammation has been proposed as a key player in mediating cellular death and destruction via poorly liganded iron (Kell, 2009). Observational studies show that risk allelic variants of single-nucleotide polymorphisms (SNPs) regulate pro-inflammatory response, in the IL-1β genetic family ( IL-1β C-511T, rs16944 ), promotes shrinkage in both gray and white matter of the brain parenchyma (Persson et al, 2014; Fornage et al, 2008). This is interesting given recent findings of correspondence between shrinkage in brain volumes and rise of MRI estimates of iron (Hagemeier et al, 2013; Peran et al, 2009), and that poorly liganded iron can cause synchronized inhibition of the genetic expression of 1L-1 β (Small et al, 2011).…”

“…Brain aging is characterized by a regional shrinkage across multiple gray and white matter regions of the brain parenchyma (Persson et al, 2014; Fjell & Walhovd, 2010), as well as a decline in the dopamine synthesis of subcortical nuclei (Seeman et al, 1987; Severson, Marcusson, Winblad, & Finch, 1982; Wang et al, 1998; Volkow et al, 1998). As the brain ages, non-heme iron accumulates across brain structures (Hallgren & Sourander, 1958).…”

The Affective Neuroscience of Aging

“…In the other one, the insula showed substantially more shrinkage longitudinally but was also identified as the brain region with the most individual differences in longitudinal change across those studied (Persson et al, 2014). This high degree of individual difference in change may also help explain differences in findings across studies.…”

Regional brain shrinkage and change in cognitive performance over two years: The bidirectional influences of the brain and cognitive reserve factors

“…However the trajectories of age-related change vary among individuals (Raz, Ghisletta, Rodrigue, Kennedy, & Lindenberger, 2010), brain regions (Fjell et al, 2009; Persson et al, 2014; Raz et al, 2005; Resnick, Pham, Kraut, Zonderman, & Davatzikos, 2003) and cognitive domains (de Frias, Lövdén, Lindenberger, & Nilsson, 2007; Ghisletta & Lindenberger, 2003; Rabbitt, 1993). …”

“…The concept of brain reserve has been advanced to explain individual differences in resilience to trauma and neurodegeneration by greater initial number of neurons and synapses (Katzman et al, 1988) as well as greater gross brain volume (Satz, 1993). Numerous cardiovascular and pro-inflammatory risk factors have been implicated in exacerbating the neural and cognitive declines observed in normal aging (Anstey & Christensen, 2000; Bettcher & Kramer, 2014; Convit, Wolf, Tarshish, & De Leon, 2003; Ghisletta et al, 2014; Persson et al, 2014; Raz et al, 2005, 2010,2013; Whalley, Deary, Appleton, & Starr, 2004). …”