Brain aging research relies mostly on cross-sectional studies, which infer true changes from age differences. We present longitudinal measures of five-year change in the regional brain volumes in healthy adults. Average and individual differences in volume changes and the effects of age, sex and hypertension were assessed with latent difference score modeling. The caudate, the cerebellum, the hippocampus and the association cortices shrunk substantially. There was minimal change in the entorhinal and none in the primary visual cortex. Longitudinal measures of shrinkage exceeded cross-sectional estimates. All regions except the inferior parietal lobule showed individual differences in change. Shrinkage of the cerebellum decreased from young to middle adulthood, and increased from middle adulthood to old age. Shrinkage of the hippocampus, the entorhinal cortices, the inferior temporal cortex and the prefrontal white matter increased with age. Moreover, shrinkage in the hippocampus and the cerebellum accelerated with age. In the hippocampus, both linear and quadratic trends in incremental age-related shrinkage were limited to the hypertensive participants. Individual differences in shrinkage correlated across some regions, suggesting common causes. No sex differences in age trends except for the caudate were observed. We found no evidence of neuroprotective effects of larger brain size or educational attainment.

Aging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44-77 years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP) -286 C>A>T, and interleukin-1β (IL-1β) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1β -511T allele and carriers of CRP -286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities.

Advanced age is associated with decline in many areas of cognition as well as increased frequency of vascular disease. Well-described risk factors for vascular disease such as diabetes and arterial hypertension have been linked to cognitive deficits beyond those associated with aging. To examine whether vascular health indices such as fasting blood glucose levels and arterial pulse pressure can predict subtle deficits in age-sensitive abilities, we studied 104 healthy adults (age 18 to 78 years) without diagnoses of diabetes or hypertension. Whereas results revealed a classic pattern of agerelated differences in cognition, pre-prandial blood glucose level and pulse pressure independently and differentially affected cognitive performance. High-normal blood glucose levels were associated with decreased delayed associative memory, reduced accuracy of working memory processing among women, and slower working memory processing among men. Elevated pulse pressure was associated with slower perceptual-motor processing. Results suggest that blood glucose levels and pulse pressure may be sensitive indicators of cognitive status in healthy adults however longitudinal research is needed to determine whether such relatively mild elevations in this select group predict age-related cognitive declines. Keywordsaging; glucose; memory; executive functions; speed of processing Advanced age is associated with moderate reduction of performance in multiple areas of cognition, with only few being spared (Horn, 1986). In nondemented older adults, measurable declines are noted in declarative memory (Verhaeghen, Marcoen, & Goossens, 1993), executive functions (West, 1996), and speed of processing (Salthouse, 1993(Salthouse, , 1996, although verbal reasoning skills may remain intact well into the late part of the lifespan (Alwin & McCammon, 2001). The cumulative research of the past decade indicates that cognitive change is not attributable exclusively to "old age," but is affected and modified by many factors associated with aging. One of the most significant modifiers of course of cognitive aging is vascular disease. Multiple studies indicate that cardiovascular risk factors become more prominent with age and exacerbate age-related cognitive declines (Elias et al., 1997;Fontbonne, Berr, Ducimetière, & Alpérovitch, 2001; Hiltunen, Keinänen-Kiukaanniemi, & Läärä, 2001;Kuusisto et al., 1993;Meyer, Rauch, Rauch, & Haque, 2000). Hyperglycemia (Kaplan, Greenwood, Winocur, & Wolever, 2000;Rolandsson, Backeström, Eriksson, Hallmans, & Nilsson, 2008;Vanhanen et al., 1997) Singh-Manoux & Marmot, 2005) are the most common vascular risk factors associated with cognitive deficits in ostensibly healthy individuals.Although vascular risk may be assessed through multiple indices, increased arterial stiffness has been identified as a major contributor to cardiovascular mortality as well as cerebrovascular morbidity (Franklin, Jacobs, Wong, L'Italien, & Lapuerta, 2001;O'Rourke, 2007;Schiffrin, 2004). One of the more convenient and valid indices ...

The hippocampus is one of the most age-sensitive brain regions, yet the mechanisms of hippocampal shrinkage remain unclear. Recent studies suggest that hippocampal subfields are differentially vulnerable to aging and differentially sensitive to vascular risk. Promoters of inflammation are frequently proposed as major contributors to brain aging and vascular disease but their effects on hippocampal subfields are unknown. We examined the associations of hippocampal subfield volumes with age, a vascular risk factor (hypertension), and genetic polymorphisms associated with variation in pro-inflammatory cytokines levels (IL-1β C-511T and IL-6 C-174G) and risk for Alzheimer’s disease (APOEε4) in healthy adult volunteers (N = 80; age = 22-82 years). Volumes of three hippocampal subfields, cornu ammonis (CA) 1-2, CA3-dentate gyrus, and the subiculum were manually measured on high-resolution magnetic resonance images. Advanced age was differentially associated with smaller volume of CA1-2, whereas carriers of the T allele of IL-1β C-511T polymorphism had smaller volume of all hippocampal subfields than CC homozygotes did. Neither of the other genetic variants, nor diagnosis of hypertension was associated with any of the measured volumes. The results support the notion that volumes of age-sensitive brain regions may be affected by pro-inflammatory factors that may be targeted by therapeutic interventions.

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.