Brain volumes in late life: gender,hormone treatment,and estrogen receptor variants

Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.     

Structural MRI covariance patterns associated with normal aging and neuropsychological functioning

Structural magnetic resonance imaging (MRI) studies have shown dramatic age-associated changes in grey and white matter volume, but typically use univariate analyses that do not explicitly test the interrelationship among brain regions. The current study used a multivariate approach to identify covariance patterns of grey and white matter tissue density to distinguish older from younger adults. A second aim was to examine whether the expression of the age-associated covariance topographies is related to performance on cognitive tests affected by normal aging. Eighty-four young (mean age=24.0) and 29 older (mean age=73.1) participants were scanned with a 1.5T MRI machine and assessed with a cognitive battery. Images were spatially normalized and segmented to produce grey and white matter density maps. A multivariate technique, based on the subprofile scaling model, was used to capture sources of between- and within-group variation to produce a linear combination of principal components that represented a "pattern" or "network" that best discriminated between the two age groups. Univariate analyses were also conducted with statistical parametric maps. Grey and white matter covariance patterns were identified that reliably discriminated between the groups with greater than 0.90 sensitivity and specificity. The identified patterns were similar for the univariate and multivariate techniques, and involved widespread regions of the cortex and subcortex. Age and the expression of both patterns were significantly associated with performance on tests of attention, language, memory, and executive functioning. The results suggest that identifiable networks of grey and white matter regions systematically decline with age and that pattern expression is linked to age-related cognitive decline.     

Preliminary evidence that long-term estrogen use reduces white matter loss in aging

Despite numerous studies showing neurotrophic and neuroprotective effects of estrogen in animal models, the long-term effects of estrogen use on brain morphology in older women are not known. Thus, we compared ventricular, cerebrospinal fluid, white matter, and grey matter volumes estimated from magnetic resonance images of postmenopausal women with more than 20 years exposure to unopposed estrogen, women who were not on estrogen, and young healthy women. Estrogen users had significantly smaller ventricles and greater white matter volumes than non-users, but hormone exposure did not affect grey matter volumes. Young healthy women had significantly smaller ventricles, less cerebrospinal fluid and more grey matter than both groups of older women. However, they had comparable white matter volumes to older women on estrogen. These findings suggest that long-term estrogen protects against white matter loss in aging. This adds to findings from other studies suggesting estrogen is neuroprotective of the hippocampus and other regions in older women.     

Global and local development of gray and white matter volume in normal children and adolescents

Over the last decade, non-invasive, high-resolution magnetic resonance imaging has allowed investigating normal brain development. However, much is still not known in this context, especially with regard to regional differences in brain morphology between genders. We conducted a large-scale study utilizing fully automated analysis-approaches, using high-resolution MR-imaging data from 200 normal children and aimed at providing reference data for future neuroimaging studies. Global and local aspects of normal development of gray and white matter volume were investigated as a function of age and gender while covarying for known nuisance variables. Global developmental patterns were apparent in both gray and white matter, with gray matter decreasing and white matter increasing significantly with age. Gray matter loss was most pronounced in the parietal lobes and least in the cingulate and in posterior temporal regions. White matter volume gains with age were almost uniform, with an accentuation of the pyramidal tract. Gender influences were detectable for both gray and white matter. Voxel-based analyses confirmed significant differences in brain morphology between genders, like a larger amygdala in boys or a larger caudate in girls. We could demonstrate profound influences of both age and gender on normal brain morphology, confirming and extending earlier studies. The knowledge of such influence allows for the consideration of age- and gender-effects in future pediatric neuroimaging studies and advances our understanding of normal and abnormal brain development.     

Effects of age and sex on volumes of the thalamus, pons, and cortex

Volumes of thalamus, pons, cortical gray matter, and white matter were derived from MR brain images of healthy men and women spanning the adult age range in order to delineate patterns of aging and to compare age and sex effects in thalamus and pons with such effects in cortical gray and white matter volumes. Men had larger intracranial volume (ICV) than women, but ICV did not correlate with age in either sex. Thalamic, pontine, and cortical white matter volumes did not differ between men and women once ICV differences were taken into account, but men had more cortical gray matter than women even after accounting for ICV. Volumes of pons and thalamus were associated, independent of ICV, in women but not in men. Thalamic volume declined linearly with age at a similar rate in both men and women, whereas cortical gray matter volume declined more steeply with age in men than women. Both pontine and cortical white matter volumes remained stable across the age span in both men and women.     

The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease

We investigated whether the val(158)met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n=80, ages 18-79) and those with Parkinson's disease (n=50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val(158)met genotype on morphometry. Since the val(158)met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.     

Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study

The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.     

Measures of brain morphology and infarction in the framingham heart study: establishing what is normal

Numerous anatomical and brain imaging studies find substantial differences in brain structure between men and women across the span of human aging. The ability to extend the results of many of these studies to the general population is limited, however, due to the generally small sample size and restrictive health criteria of these studies. Moreover, little attention has been paid to the possible impact of brain infarction on age-related differences in regional brain volumes. Given the current lack of normative data on gender and aging related differences in regional brain morphology, particularly with regard to the impact of brain infarctions, we chose to quantify brain MRIs from more than 2200 male and female participants of the Framingham Heart Study who ranged in age from 34 to 97 years. We believe that MRI analysis of the Framingham Heart Study more closely represents the general population enabling more accurate estimates of regional brain changes that occur as the consequence of normal aging. As predicted, men had significantly larger brain volumes than women, but these differences were generally not significant after correcting for gender related differences in head size. Age explained approximately 50% of total cerebral brain volume differences, but age-related differences were generally small prior to age 50, declining substantially thereafter. Frontal lobe volumes showed the greatest decline with age (approximately 12%), whereas smaller differences were found for the temporal lobes (approximately 9%). Age-related differences in occipital and parietal lobe were modest. Age-related gender differences were generally small, except for the frontal lobe where men had significantly smaller lobar brain volumes throughout the age range studied. The prevalence of MRI infarction was common after age 50, increased linearly with age and was associated with significantly larger white matter hyperintensity (WMH) volumes beyond that associated with age-related differences in these measures. Amongst men, the presence of MRI infarction was associated with significant age-related reductions in total brain volume. Finally, statistically significant associations were found between the volume of MRI infarcts in cubic centimeters and all brain measures with the exception of parietal lobe volume for individuals where the volume of MRI infarctions was measured. These data serve to define age and gender differences in brain morphology for the Framingham Heart Study. To the degree participants of the Framingham Heart Study are representative the general population, these data can serve as norms for comparison with morphological brain changes associated with aging and disease. In this regard, these cross-sectional quantitative estimates suggest that age-related tissue loss differs quantitatively and qualitatively across brain regions with only minor differences between men and women. In addition, MRI evidence of cerebrovascular disease is common to the aging process and associated with smaller regional brain volumes for a given age, particularly for men. We believe quantitative MRI studies of the Framingham community enables exploration of numerous issues ranging from understanding normal neurobiology of brain aging to assessing the impact of various health factors, particularly those related to cerebrovascular disease, that appear important to maintaining brain health for the general population.     

Age-specific MRI templates for pediatric neuroimaging

This study created a database of pediatric age-specific magnetic resonance imaging (MRI) brain templates for normalization and segmentation. Participants included children from 4.5 through 19.5 years, totaling 823 scans from 494 subjects. Open-source processing programs (FMRIB Software Library, Statistical Parametric Mapping, Advanced Normalization Tools [ANTS]) constructed head, brain, and segmentation templates in 6-month intervals. The tissue classification (white matter [WM], gray matter [GM], cerebrospinal fluid) showed changes over age similar to previous reports. A volumetric analysis of age-related changes in WM and GM based on these templates showed expected increase/decrease pattern in GM and an increase in WM over the sampled ages. This database is available for use for neuroimaging studies (http://jerlab.psych.sc.edu/neurodevelopmentalmridatabase).     

Cognitive and neural plasticity in old age: A systematic review of evidence from executive functions cognitive training

Cognitive training is a popular intervention aimed at attenuating age-related cognitive decline, however, the effects of this intervention on brain structure and function have not been thoroughly explored. Core executive functions (working memory, inhibition, cognitive flexibility) are dependent upon prefrontal brain regions—one of the most vulnerable areas of age-related decline. They are also implicated in numerous cognitive processes and higher-order functions. Training executive functions should therefore promote cognitive and neural enhancements in old age. This systematic review examined the effects of executive functions training on brain and cognition amongst healthy older adults across 20 studies. Behavioral performance consistently improved on trained cognitive tasks, though mixed findings were reported for untrained tasks. Training-related structural changes were reported, evidenced through increases in grey matter and cortical volume. Functional changes were not consistent, though a general pattern of increased subcortical and decreased frontal and parietal activation emerged across studies, indicating that training may potentially reduce reliance on compensatory neural mechanisms. Training executive functions appears to promote cognitive and neural plasticity in old age, though further research is required to develop a more comprehensive framework which connects and elucidates the mechanisms underlying cognitive training, cognitive transfer, and cognitive aging.     

Adult age differences in the functional neuroanatomy of visual attention: a combined fMRI and DTI study

We combined measures from event-related functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and cognitive performance (visual search response time) to test the hypotheses that differences between younger and older adults in top-down (goal-directed) attention would be related to cortical activation, and that white matter integrity as measured by DTI (fractional anisotropy, FA) would be a mediator of this age-related effect. Activation in frontal and parietal cortical regions was overall greater for older adults than for younger adults. The relation between activation and search performance supported the hypothesis of age differences in top-down attention. When the task involved top-down control (increased target predictability), performance was associated with frontoparietal activation for older adults, but with occipital (fusiform) activation for younger adults. White matter integrity (FA) exhibited an age-related decline that was more pronounced for anterior brain regions than for posterior regions, but white matter integrity did not specifically mediate the age-related increase in activation of the frontoparietal attentional network.     

Grey and white matter GABA level differences in the human brain using two-dimensional, J-resolved spectroscopic imaging

A novel, two-dimensional, J-resolved chemical-shift imaging sequence was used to collect gamma-aminobutyric acid (GABA) spectroscopic imaging data on six healthy subjects at 4 T. Using image segmentation and a linear-regression analysis relating brain GABA level to tissue-type, a consistent and significant (n = 6, p < 0.01) elevation of mean GABA levels was measured in the cortical grey matter (0.96 +/- 0.24 mm) compared with white matter (0.44 +/- 0.16 mm) across all six subjects. The results suggest an approximately two-fold elevation of GABA levels in cortical grey matter compared with white matter in vivo. Our findings are consistent with ex vivo studies in the literature of both animal and human brain and demonstrate the significant potential of this technique for detecting and quantifying tissue-specific neurochemical pathology in vivo.     

Neuroimaging of cortical development and brain connectivity in human newborns and animal models

Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype.     

Fractional anisotropy of water diffusion in cerebral white matter across the lifespan

Determining the time of peak of cerebral maturation is vital for our understanding of when cerebral maturation ceases and the cerebral degeneration in healthy aging begins. We carefully mapped changes in fractional anisotropy (FA) of water diffusion for eleven major cerebral white matter tracts in a large group (831) of healthy human subjects aged 11-90. FA is a neuroimaging index of micro-structural white matter integrity, sensitive to age-related changes in cerebral myelin levels, measured using diffusion tensor imaging. The average FA values of cerebral white matter (WM) reached peak at the age 32 ± 6 years. FA measurements for all but one major cortical white matter tract (cortico-spinal) reached peaks between 23 and 39 years of age. The maturation rates, prior to age-of-peak were significantly correlated (r = 0.74; p = 0.01) with the rates of decline, past age-of-peak. Regional analysis of corpus callosum (CC) showed that thinly-myelinated, densely packed fibers in the genu, that connect pre-frontal areas, maturated later and showed higher decline in aging than the more thickly myelinated motor and sensory areas in the body and splenium of CC. Our findings can be summarized as: associative, cerebral WM tracts that reach their peak FA values later in life also show progressively higher age-related decline than earlier maturing motor and sensory tracts. These findings carry multiple and diverse implications for both theoretical studies of the neurobiology of maturation and aging and for the clinical studies of neuropsychiatric disorders.     

Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C

Background and purposeCerebellar Purkinje cells are known to be highly vulnerable to neuronal pathology in Niemann-Pick type C (NPC), a disease where widespread white matter changes have also been reported. We sought to determine the relationship between white and grey matter cerebellar changes and clinical variables in NPC.Materials and methodsTen adult patients with NPC were matched to control subjects (n = 27) on age and gender. Patients were rated for symptom duration and severity, degree of ataxia, and were assessed for saccadic eye measures. Cerebellar white and grey matter volumes were automatically segmented using the Freesurfer software package.ResultsNPC patients had a significant reduction in both grey and white matter volumes. Volume did not correlate with symptom duration or severity, but did correlate with saccadic gain and ataxia measures.ConclusionsBoth cerebellar grey and white matter volume decreases in adult NPC, and these changes are associated with impairments in saccadic gain and in motor control.     

Staging Alzheimer's disease progression with multimodality neuroimaging

Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer's disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms.     

Differential and subtype-specific neuroimaging abnormalities in amnestic and nonamnestic mild cognitive impairment: A systematic review and meta-analysis

While mild cognitive impairment (MCI) has been classified into amnestic MCI (aMCI) and nonamnestic MCI (naMCI), the neuropathological bases of these two subtypes remain elusive. Here, we performed a systematic review and meta-analysis to determine the subtype specificity of neuroimaging abnormalities in MCI and to identify neural features that may differ between aMCI and naMCI. We synthesized 50 studies that used common neuroimaging modalities, including magnetic resonance imaging and positron emission tomography, to compare brain atrophy, white matter abnormalities, cortical thinning, cerebral hypometabolism, amyloid/tau deposition, or other features among aMCI, naMCI, and normal cognition. Compared with normal cognition, aMCI shows diverse neuroimaging abnormalities of large effect sizes. In contrast, naMCI exhibits restricted abnormalities of small effect sizes. Some features, including medial temporal lobe atrophy and white matter abnormalities, are shared by the two MCI subtypes. Overall, brain abnormalities are worse, if not similar, in aMCI than in naMCI. The only neuroimaging abnormality specific to aMCI is increased amyloid burden; no feature specific to naMCI was found. Taken together, our findings have elucidated the neuropathological changes that occur in aMCI and naMCI. Clarifying the neuroimaging profiles of aMCI and naMCI can improve the early identification, differentiation, and intervention of prodromal dementia.     

Age-Specific MRI Templates for Pediatric Neuroimaging

This study created a database of pediatric age-specific magnetic resonance imaging (MRI) brain templates for normalization and segmentation. Participants included children from 4.5 through 19.5 years, totaling 823 scans from 494 subjects. Open-source processing programs (FMRIB Software Library, Statistical Parametric Mapping, Advanced Normalization Tools [ANTS]) constructed head, brain, and segmentation templates in 6-month intervals. The tissue classification (white matter [WM], gray matter [GM], cerebrospinal fluid) showed changes over age similar to previous reports. A volumetric analysis of age-related changes in WM and GM based on these templates showed expected increase/decrease pattern in GM and an increase in WM over the sampled ages. This database is available for use for neuroimaging studies (http://jerlab.psych.sc.edu/neurodevelopmentalmridatabase).     

Aging in deep gray matter and white matter revealed by diffusional kurtosis imaging

Diffusion tensor imaging has already been extensively used to probe microstructural alterations in white matter tracts, and scarcely, in deep gray matter. However, results in literature regarding age-related degenerative mechanisms in white matter tracts and parametric changes in the putamen are inconsistent. Diffusional kurtosis imaging is a mathematical extension of diffusion tensor imaging, which could more comprehensively mirror microstructure, particularly in isotropic tissues such as gray matter. In this study, we used the diffusional kurtosis imaging method and a white-matter model that provided metrics of explicit neurobiological interpretations in healthy participants (58 in total, aged from 25 to 84 years). Tract-based whole-brain analyses and regions-of-interest (anterior and posterior limbs of the internal capsule, cerebral peduncle, fornix, genu and splenium of corpus callosum, globus pallidus, substantia nigra, red nucleus, putamen, caudate nucleus, and thalamus) analyses were performed to examine parametric differences across regions and correlations with age. In white matter tracts, evidence was found supportive for anterior–posterior gradient and not completely supportive for retrogenesis theory. Age-related degenerations appeared to be broadly driven by axonal loss. Demyelination may also be a major driving mechanism, although confined to the anterior brain. In terms of deep gray matter, higher mean kurtosis and fractional anisotropy in the globus pallidus, substantia nigra, and red nucleus reflected higher microstructural complexity and directionality compared with the putamen, caudate nucleus, and thalamus. In particular, the unique age-related positive correlations for fractional anisotropy, mean kurtosis, and radial kurtosis in the putamen opposite to those in other regions call for further investigation of exact underlying mechanisms. In summary, the results suggested that diffusional kurtosis can provide measurements in a new dimension that were complementary to diffusivity metrics. Kurtosis together with diffusivity can more comprehensively characterize microstructural compositions and age-related changes than diffusivity alone. Combined with proper model, it may also assist in providing neurobiological interpretations of the identified alterations.     

Age-related gray matter volume changes in the brain during non-elderly adulthood

Previous magnetic resonance imaging (MRI) studies described consistent age-related gray matter (GM) reductions in the fronto-parietal neocortex, insula and cerebellum in elderly subjects, but not as frequently in limbic/paralimbic structures. However, it is unclear whether such features are already present during earlier stages of adulthood, and if age-related GM changes may follow non-linear patterns at such age range. This voxel-based morphometry study investigated the relationship between GM volumes and age specifically during non-elderly life (18-50 years) in 89 healthy individuals (48 males and 41 females). Voxelwise analyses showed significant (p < 0.05, corrected) negative correlations in the right prefrontal cortex and left cerebellum, and positive correlations (indicating lack of GM loss) in the medial temporal region, cingulate gyrus, insula and temporal neocortex. Analyses using ROI masks showed that age-related dorsolateral prefrontal volume decrements followed non-linear patterns, and were less prominent in females compared to males at this age range. These findings further support for the notion of a heterogeneous and asynchronous pattern of age-related brain morphometric changes, with region-specific non-linear features.