Frontal connections and cognitive changes in normal aging rhesus monkeys: A DTI study
Introduction
Studies using non-human primate models of normal aging have provided evidence of a pattern of age-related cognitive decline in memory and executive function similar to humans (e.g. Albert and Moss [2] and Herndon [33]). Examinations of the brains of these behaviorally characterized young and old monkeys has demonstrated that cortical neurons are largely preserved in the cerebral cortex, including primary motor cortex (area 4), primary visual cortex (area 17), and prefrontal association cortex (area 46) (see Peters et al. [60] and Peters and Rosene [61]), while a variety of degenerative changes are observed in forebrain white matter including myelin breakdown, loss of myelin and even mild loss of axons (e.g. Peters et al. [62], Sandell and Peters [79], and Peters and Rosene [61]). Anatomical studies in humans also indicate that neuron numbers are preserved in the cerebral cortex [29], [32], [55], while white matter is lost [44]. While these types of histological examinations are critical for examining the microstructures of the brain, because they are so labor intensive, they can only sample limited brain regions. In this regard, magnetic resonance imaging (MRI) offers a number of modalities that can provide global in vivo assessments of the various components of the brain such as the integrity of the white matter. In humans, MRI has been used to show an overall volume reduction in white matter in subjects ranging in age from 18 to 88 years [31]. When the same segmentation techniques were applied to the monkey, an overall decline in white matter volume is also detected [61] and morphological studies in humans and monkeys have confirmed a loss of white matter and myelinated axons [44], [79]. Whether these changes in white matter reflect a ubiquitous change or a topographically specific process is unknown. To address this question we have employed Diffusion Tensor MRI (DT-MRI), which enables us to assess the integrity of white matter fibers by measuring the three-dimensional self-diffusion of water along the axons.
DT-MRI yields data on scalar metrics of fractional anisotropy (FA) and lattice anisotropy (LA). FA is the most commonly used of the two metrics [73]. FA is a calculated measure that is dependent on the orientational coherence of the diffusion compartments within a voxel. FA is thought to provide an index of the restrictional microstructure in the white matter and is measured in terms of its index. FA has a value of 0 for isotropic diffusion (e.g. minimally organized restriction in a single orientation, as in regions with crossing fibers) and a value of 1 for maximally anisotropic diffusion (e.g. maximally organized restriction in a single orientation, as in the internal capsule). Group differences in FA values of similar anatomical regions would suggest a difference in the white matter microenvironment. For example, lower fiber density or decreased orientation specificity would result in less tightly packed fiber bundles, and thus, water diffusion would be less restricted and FA values would be lower.
FA has been used to examine changes in white matter in multiple sclerosis [17], schizophrenia [39], alcoholism [69], [71], [72], amyotrophic lateral sclerosis [23], and other degenerative conditions in humans. Recent studies have also documented significant declines in the orientational organization of the white matter in normal and pathological aging, suggesting that DT-MRI may be a useful tool for the study of brain aging in humans [18], [50], [53], [54], [71], [72], [77], [86]. However, there are no reported studies implementing DT-MRI in aging monkeys where both behavioral assessment and subsequent histological studies can be conducted and the present is the first study investigating FA differences in the white matter of aging rhesus monkeys.
We hypothesized that in aged monkeys, structural changes of long corticocortical association fiber tracts, specifically the superior longitudinal fasciculus II (SLF II) and the cingulum bundle (CB), but not projectional fiber tracts such as the corticospinal tract (ICpl), will produce decreases in their anisotropy that can be measured using DT-MRI. Based on behavioral findings that have been reported with aging monkeys suggesting declines in prefrontal functions [1], [4], [8], [25], [30], [49], we expected anisotropy values within the frontal lobe white matter to be more severely affected. To test this hypothesis we acquired DT-MRI scans on seven young and seven aged rhesus monkeys that were behaviorally tested on tasks assessing recognition memory and executive function.
Section snippets
Subjects
The animals used for this study were obtained from the Yerkes Regional Primate Research Center at Emory University in Atlanta. They were selected according to strict health criteria designed to exclude any diseases, clinical, or experimental manipulations that might confound investigations of normal aging by adversely affecting the brain or behavior. These include any direct manipulations of the brain, history of chronic disease, history of immune system dysfunction, chronic drug treatments,
Fractional anisotropy
The mean age of the young monkey group was 9.1 years (standard deviation (S.D.) = 3.9) and the mean age of the old monkey group was 22.4 years (S.D. = 4.3) [t(12) = 6.1, p < 0.0001]. The result of the inter-group difference FA maps for the young group (n = 7) versus the old group (n = 7) is shown in Fig. 3 and Table 2. Regions of significant (young greater than old) differences in FA signal fell entirely within the anatomical ROIs for SLF II, CB and aCC. No significant differences were observed in the
Summary
The process of normal aging in humans and monkeys is characterized by mild impairments in memory and executive function. Breakdown of the integrity of the myelin sheaths of axons has been observed in monkeys in frontal and temporal areas [60], [62] and MRI studies have shown overall volume reduction in normal appearing white matter with segmentation procedures [61]. In this first study of FA differences in aging monkeys, we demonstrated that association cortico-cortical fiber pathways of the
Conclusions
Through their rich connections, the SLF II, the CB and the anterior callosal fiber systems constitute the major part of frontal lobe associational corticocortical ipsilateral and contralateral (or commissural) connections. Alteration of these systems would affect the connectivity and functional integrity of the prefrontal cortex in the aging monkey. Behavioral correlations in our study support the idea that the cognitive functions of the prefrontal cortex in the old monkeys may be diminished as
Acknowledgements
This research was supported by the National Institute on Aging (1R03-AG20829-01), the National Center for Research Resources (P41-RR14075 and P51-RR00165), the National Association for Research in Schizophrenia and Depression (NARSAD), the Amyotrophic Lateral Sclerosis Association (ALSA), and the National Center for Complementary and Alternative Medicine (NCCAM) to Dr. Nikos Makris; the National Institute on Aging (P01-AG00001) to Dr. Douglas Rosene; BRP R01-EB00790-03 for Dr. Anders M. Dale;
References (92)
Neuropsychological and neurophysiological changes in healthy adult humans across the age range
Neurobiol Aging
(1993)- et al.
Attention-deficit/hyperactivity disorder: a preliminary diffusion tensor imaging study
Biol Psychiatry
(2005) - et al.
A single case-study of diagonistic dyspraxia
Brain Cogn
(2004) - et al.
Estimation of the effective self-diffusion tensor from the NMR spin echo
J Magn Reson B
(1994) - et al.
Hemispheric specialization in nonverbal communication
Cortex
(1983) - et al.
Callosal lesions and behavior: history and modern concepts
Epilepsy Behav
(2003) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
Patterns of cognitive decline in aged rhesus monkeys
Behav Brain Res
(1997) - et al.
Distribution of visual and somatic functions in the parietal associative area 7 of the monkey
Brain Res
(1979) - et al.
Improved optimization for the robust and accurate linear registration and motion correction of brain images
Neuroimage
(2002)
A global optimisation method for robust affine registration of brain images
Med Image Anal
Robust smoothness estimation in statistical parametric maps using standardized residuals from the general linear model
Neuroimage
Impairment in abstraction and set shifting in aged rhesus monkeys
Neurobiol Aging
Social processing deficits in agenesis of the corpus callosum: narratives from the Thematic Appreciation Test
Arch Clin Neuropsychol
Frontal circuitry degradation marks healthy adult aging: evidence from diffusion tensor imaging
Neuroimage
Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women
Biol Psychiatry
Microstructural but not macrostructural disruption of white matter in women with chronic alcoholism
Neuroimage
Age-related alterations in white matter microstructure measured by diffusion tensor imaging
Neurobiol Aging
Consciousness, personal identity and the divided brain
Neuropsychologia
Profiles of normal aging
Posterior parietal cortex
Rev Oculomot Res
Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task
Psychopharmacology (Berl)
Magnetization transfer contrast in magnetic resonance imaging
Magn Reson Q
Aging in the rhesus monkey: effects on visual discrimination learning and reversal learning
J Gerontol
Controlling the false discover rate: a practical and powerful approach to multiple testing
J R Statist Soc B
Diffusion anisotropy in subcortical white matter and cortical gray matter: changes with aging and the role of CSF-suppression
J Magn Reson Imag
Neuronal activity in the lateral intraparietal area and spatial attention
Science
The role of the parietal cortex in the neural processing of saccadic eye movements
Adv Neurol
Beitrage zur histologischen lokalisation der grosshirnrinde. III. Die rindenfelder der niederen affen
J Psychol Neurol
A developmental functional MRI study of prefrontal activation during performance of a go-no-go task
J Cogn Neurosci
Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI
Neurology
White matter damage on diffusion tensor imaging correlates with age-related cognitive decline
Neurology
Automated mulit-modality image registration based on information theory
Informat Process Med Imag
Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space
J Comput Assist Tomogr
Contributions of anterior cingulate cortex to behaviour
Brain
Diffusion tensor MRI assesses corticospinal tract damage in ALS
Neurology
Examination of age-related deficits on the Wisconsin Card Sorting Test
Neuropsychology
Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition?
Brain
MRI assessment of human callosal surgery with neuropsychological correlates
Neurology
The visual and frontal cortices
Rev Oculomot Res
Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease
J Neurosci
The cognitive correlates of white matter abnormalities in normal aging: a quantitative review
Neuropsychology
White matter changes with normal aging
Neurology
Are neurons of the human cerebral cortex really lost during aging?
DTI and impulsivity in schizophrenia: a first voxelwise correlational analysis
Neuroreport
Diffusion tensor imaging and its application to neuropsychiatric disorders
Harv Rev Psychiatry
Cited by (93)
Aging in nonhuman primates
2021, Handbook of the Biology of AgingLong-term effects of curcumin in the non-human primate brain
2018, Brain Research BulletinCitation Excerpt :Studies of both humans and non-human primates have demonstrated that age-related cognitive decline begins as early as the fifth decade and typically the earliest changes occurring in the domain of executive function which is mediated by the prefrontal cortex (Cahn-Weiner et al., 2000; Fristoe et al., 1997; Lai et al., 1995; Moore et al., 2003, 2006; Hara et al., 2012; León et al., 2016). Interestingly, there is also significant evidence for age-related changes in PFC white matter and myelin (Bowley et al., 2010; Drag and Bieliauskas, 2010; Guttmann et al., 1998; Makris et al., 2007; Peters and Sethares, 2002) and it is thought that inflammation may underlie this white matter pathology and myelin breakdown and therefore anti-inflammatory comounds are potential interventions (Cornejo and von Bernhardi, 2016; Xie et al., 2013). Curcumin, a naturally occurring compound of the ginger family and the primary active ingredient in the spice turmeric, is a powerful anti-inflammatory and anti-oxidant and therefore may slow or delay progression of age-related changes in cognitive functions (Cox et al., 2015; Aggarwal and Harikumar, 2009).
Computational models
2018, Molecular-Genetic and Statistical Techniques for Behavioral and Neural Research