The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon 4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04 +/- 0.02% per year for ERC and 0.05 +/- 0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE 84 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials. (c) 2005 Elsevier Inc. All rights reserved.

/pdf/age-effects-on-atrophy-rates-of-entorhinal-cortex-and-3ofop3u3lj.pdf

Age effects on atrophy rates of entorhinal cortex and hippocampus - eScholarship

Objective To examine the association between systemic inflammation measured during midlife and 20-year cognitive decline. Methods Within the Atherosclerosis Risk in Communities cohort study, inflammatory biomarkers were measured during middle adulthood. We created an inflammation composite score using 4 blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); we measured C-reactive protein (CRP) at visit 2. Cognition was assessed over 3 visits spanning 20 years using measures of memory, executive function, and language. Results A total of 12,336 participants (baseline age 56.8 [5.7], 21% black, 56% women) were included. After adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of −0.035 SD (95% confidence interval: −0.062 to −0.007) on the cognitive composite score. We found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (−0.038 SD, 95% confidence interval: −0.057 to −0.019). Participants with a midlife inflammation composite score in the top quartile had a 7.8% steeper cognitive decline, compared to participants in the lowest quartile; CRP in the top quartile was associated with an 11.6% steeper cognitive decline. In cognitive domain-specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory. Results were similar after adjusting for attrition using inverse probability weighting. Conclusions Our findings highlight what may be an early pathogenic role for systemic inflammation as a driver of cognitive decline in the decades leading up to older adulthood.

Systemic inflammation during midlife and cognitive change over 20 years: The ARIC Study

Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later. Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm 3 greater ventricular ( p = 0.013), 110 mm 3 smaller hippocampal ( p = 0.013), 519 mm 3 smaller occipital ( p = 0.009), and 532 mm 3 smaller Alzheimer disease signature region ( p = 0.008) volumes, and reduced episodic memory ( p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. Conclusions: Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

/pdf/midlife-systemic-inflammatory-markers-are-associated-with-2bhda8ecu6.pdf

Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study

The hippocampus is a key component of emotional and memory circuits and is broadly connected throughout the brain. We tracked the whole-brain connections of white matter fibres from the hippocampus using ultra-high angular resolution diffusion MRI in both a single 1150-direction dataset and a large normal cohort (n = 94; 391-directions). Using a connectomic approach, we identified six dominant pathways in terms of strength, length and anatomy, and characterised them by their age and gender variation. The strongest individual connection was to the ipsilateral thalamus. There was a strong age dependence of hippocampal connectivity to medial occipital regions. Overall, our results concur with preclinical and ex-vivo data, confirming that meaningful in vivo characterisation of hippocampal connections is possible in an individual. Our findings extend the collective knowledge of hippocampal anatomy, highlighting the importance of the spinal-limbic pathway and the striking lack of hippocampal connectivity with motor and sensory cortices.

/pdf/revealing-the-hippocampal-connectome-through-super-26jlnxx26t.pdf

Revealing the Hippocampal Connectome through Super-Resolution 1150-Direction Diffusion MRI

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

/pdf/hippocampal-subfield-volumetry-from-structural-isotropic-1-j5xzg89d81.pdf

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

MRI has become an indispensable tool for brain volumetric studies, with the hippocampus an important region of interest. Automation of the MRI segmentation process has helped advance the field by facilitating the volumetric analysis of larger cohorts and more studies. FreeSurfer has emerged as the de facto standard tool for these analyses, but studies validating its output are all based on older versions. To characterize FreeSurfer's validity, we compare several versions of FreeSurfer software with traditional hand-tracing. Using MRI images of 262 males and 402 females aged 38 to 84, we directly compare estimates of hippocampal volume from multiple versions of FreeSurfer, its hippocampal subfield routines, and our manual tracing protocol. We then use those estimates to assess asymmetry and atrophy, comparing performance of different estimators with each other and with brain atrophy measures. FreeSurfer consistently reports larger volumes than manual tracing. This difference is smaller in larger hippocampi or older people, with these biases weaker in version 6.0.0 than prior versions. All methods tested agree qualitatively on rightward asymmetry and increasing atrophy in older people. FreeSurfer saves time and money, and approximates the same atrophy measures as manual tracing, but it introduces biases that could require statistical adjustments in some studies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hbm.24017

A comparison of manual tracing and FreeSurfer for estimating hippocampal volume over the adult lifespan.

Objectives
To quantify associations between inflammatory biomarkers and hippocampal volume (HV) and to examine effect modification according to sex, race, and age.

Design
Cross-sectional analyses using generalized estimating equations to account for familial clustering; standardized β-coefficients adjusted for age, sex, race, and education.

Setting
Community cohorts in Jackson, Mississippi and Rochester, Minnesota.

Participants
The Genetic Epidemiology Network of Arteriopathy study.

Measurements
C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors 1 (sTNFR-1) and 2 (sTNFR-2) from peripheral blood were measured in a sample of 773 non-Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV.

Results
In the full sample, higher sTNFR-1 and sTNFR-2 were associated with smaller HV. Each standard deviation (SD) increase in sTNFR-1 was associated with 59.1 mm3 (95% confidence interval (CI) = −101.4 to −16.7 mm3) smaller HV and each SD increase in sTNFR-2 associated with 48.8 mm3 (95% CI = −92.2 to −5.3 mm3) smaller HV. Relationships were stronger for sTNFR-2 in men (HV = −116.6 mm3 for each SD increase, 95% CI = −201.0 to −32.1) than women (HV = −26.0 per SD increase, 95% CI = −72.4–20.5) and sTNFR-1 in non-Hispanic whites (HV = −84.7 mm3 per SD increase, 95% CI = −142.2 to −27.1) than African Americans (HV = −14.1 mm3 per SD increase, 95% CI = −78.3–50.1). Associations between IL-6 or CRP and HV were not supported.

Conclusion
Higher levels of sTNFRs were associated cross-sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late-life cognitive impairment.

Associations Between Serum Inflammatory Markers and Hippocampal Volume in a Community Sample.

In the News Focus story “Waiting for the revolution” (4 February, p. [526][1]), E. Marshall discussed the use of genetic diagnostics in medicine. However, an analysis of the medical genetics revolution should focus not only on diagnostics but also on genetic manipulation.

The genetic revolution is well under way in microbes and invertebrates. It's even enjoying great progress in mice and moderate progress in rats. The real progress in these organisms has come not from the ability to read their genes; rather, it is a result of our ability to write them.

Improving modern treatments, including pharmaceuticals, based on genetic differences is certainly a valuable addition to our medical toolbox. But I predict that the advent of genetic manipulations in humans—whether in embryos or in adults, whether transient or permanent, whether purely genetic or epigenetic—will be considered the real beginning of the genetic revolution.

Before we proceed down this road, we must address numerous risks and ethical questions. But we cannot experience any sort of genetic revolution in human medicine until we push through these obstacles and address the benefits to humanity of repairing the aberrantly expanded HTT gene in a middle-aged Huntington's patient or knocking in a copy of the CFTR gene in a child suffering from cystic fibrosis. Diagnostics are just viewing the toolbox through a window. Eventually, we'll need to figure out how to safely pick up the tools and make good use of them.

 [1]: /lookup/doi/10.1126/science.331.6017.526

Mike F. Schmidt

Papers

A comparison of manual tracing and FreeSurfer for estimating hippocampal volume over the adult lifespan.

Associations Between Serum Inflammatory Markers and Hippocampal Volume in a Community Sample.

Genomic Medicine: Putting Our Tools to Use

53. The Anterior Hippocampus and the Pathogenesis of Major Depression