White matter integrity correlates of implicit sequence learning in healthy aging

Previous research has identified subcortical (caudate, putamen, hippocampus) and cortical (dorsolateral prefrontal cortex, DLPFC; frontal motor areas) regions involved in implicit sequence learning, with mixed findings for whether these neural substrates differ with aging. The present study used diffusion tensor imaging (DTI) tractography to reconstruct white matter connections between the known gray matter substrates, and integrity of these tracts was related to learning in the alternating serial reaction time task (ASRT) in younger and healthy older adults. Both age groups showed significant sequence learning (better performance to predictable, frequently occurring vs. less frequent events), with an age-related difference in the late learning stage. Caudate-DLPFC and hippocampus-DLPFC tract integrity were related to ASRT sequence learning, and these brain-behavior relationships did not differ significantly between age groups. Additionally, age-related decreases in caudate-DLPFC tract integrity mediated age-related differences in late stage sequence learning. Together, these findings complement studies of gray matter substrates underlying implicit sequence learning, and provide evidence for similar white matter integrity-sequence learning relationships in younger and healthy older adults.     

White matter tract integrity predicts visual search performance in young and older adults

Functional imaging research has identified frontoparietal attention networks involved in visual search, with mixed evidence regarding whether different networks are engaged when the search target differs from distracters by a single (elementary) versus multiple (conjunction) features. Neural correlates of visual search, and their potential dissociation, were examined here using integrity of white matter connecting the frontoparietal networks. The effect of aging on these brain-behavior relationships was also of interest. Younger and older adults performed a visual search task and underwent diffusion tensor imaging (DTI) to reconstruct 2 frontoparietal (superior and inferior longitudinal fasciculus; SLF and ILF) and 2 midline (genu, splenium) white matter tracts. As expected, results revealed age-related declines in conjunction, but not elementary, search performance; and in ILF and genu tract integrity. Importantly, integrity of the superior longitudinal fasciculus, ILF, and genu tracts predicted search performance (conjunction and elementary), with no significant age group differences in these relationships. Thus, integrity of white matter tracts connecting frontoparietal attention networks contributes to search performance in younger and older adults.     

White matter fractional anisotropy predicts balance performance in older adults

Aging is characterized by brain structural changes that may compromise motor functions. In the context of postural control, white matter integrity is crucial for the efficient transfer of visual, proprioceptive and vestibular feedback in the brain. To determine the role of age-related white matter decline as a function of the sensory feedback necessary to correct posture, we acquired diffusion weighted images in young and old subjects. A force platform was used to measure changes in body posture under conditions of compromised proprioceptive and/or visual feedback. In the young group, no significant brain structure-balance relations were found. In the elderly however, the integrity of a cluster in the frontal forceps explained 21% of the variance in postural control when proprioceptive information was compromised. Additionally, when only the vestibular system supplied reliable information, the occipital forceps was the best predictor of balance performance (42%). Age-related white matter decline may thus be predictive of balance performance in the elderly when sensory systems start to degrade.     

Microstructural changes and atrophy in brain white matter tracts with aging

Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography was used to investigate microstructural and volumetric abnormalities of the major brain white matter (WM) tracts with aging in 84 healthy subjects. Linear relationships were found between age and mean diffusivity (MD) increase and fractional anisotropy (FA) decrease in all WM tracts, except the right cingulum and bilateral uncinate, where a linear correlation with age was found for FA only. Quadratic model fitted better MD and FA values of several tracts, including the corpus callosum, limbic pathways, and bilateral association, and corticospinal tracts. Age-related MD and FA abnormalities were associated with radial diffusivity increase in all WM tracts, while axial diffusivity changes were characterized by a considerable variation from a tract to another. A linear negative relationship with age was found for the volumes of the left cingulum and fornix, while the quadratic model fitted better age-related volume loss of corpus callosum and right inferior fronto-occipital fasciculus. Diffusion tensor magnetic resonance imaging may shed light into the complex pathological substrates of WM changes with aging.     

White matter hyperintensities alter functional organization of the motor system

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.     

A genome-wide search for genetic influences and biological pathways related to the brain's white matter integrity

A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ～73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 × 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 × 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA).     

Age-related decline in white matter tract integrity and cognitive performance: A DTI tractography and structural equation modeling study

Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.     

White matter deterioration in 15 months: latent growth curve models in healthy adults

The goal of the study was to examine the differences in trajectories of change in the volume of white matter hyperintensities (WMH) in healthy adults within a relatively short period. We measured volumes of periventricular and deep WMH in frontal, temporal, parietal, and occipital lobes of healthy volunteers (age 49-83) on 3 occasions, approximately 15 months apart. At baseline, 40 participants underwent magnetic resonance imaging (MRI), 37 returned for the first and 30 for the second follow-up. Latent growth curve models estimated the variance and mean change in WMH volume and examined their associations with age, sex, education, and hypertension. In both regions and for both WMH types, the positive association between volume and age was stronger among the middle-aged adults and became weaker in older ages, as a logarithmic function of age. Individual variations were present in initial WMH volume but not in WMH volume progression. Frontal deep WMH volume was greater in hypertensive participants, whereas lower education was associated with greater posterior deep WMH volume. Thus, white matter of healthy middle-aged and older adults undergoes significant regional deterioration in a relatively short period, and is negatively affected by vascular risk and lower educational level.     

Effects of sustained cognitive activity on white matter microstructure and cognitive outcomes in healthy middle-aged adults: A systematic review

Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes.     

Accelerated white matter aging in schizophrenia: role of white matter blood perfusion

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18–63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia.     

Non-Gaussian water diffusion in aging white matter

Age-associated white matter degeneration has been well documented and is likely an important mechanism contributing to cognitive decline in older adults. Recent work has explored a range of noninvasive neuroimaging procedures to differentially highlight alterations in the tissue microenvironment. Diffusional kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI) that accounts for non-Gaussian water diffusion and can reflect alterations in the distribution and diffusion properties of tissue compartments. We used DKI to produce whole-brain voxel-based maps of mean, axial, and radial diffusional kurtoses, quantitative indices of the tissue microstructure's diffusional heterogeneity, in 111 participants ranging from the age of 33 to 91 years. As suggested from prior DTI studies, greater age was associated with alterations in white-matter tissue microstructure, which was reflected by a reduction in all 3 DKI metrics. Prominent effects were found in prefrontal and association white matter compared with relatively preserved primary motor and visual areas. Although DKI metrics co-varied with DTI metrics on a global level, DKI provided unique regional sensitivity to the effects of age not available with DTI. DKI metrics were additionally useful in combination with DTI metrics for the classification of regions according to their multivariate “diffusion footprint”, or pattern of relative age effect sizes. It is possible that the specific multivariate patterns of age-associated changes measured are representative of different types of microstructural pathology. These results suggest that DKI provides important complementary indices of brain microstructure for the study of brain aging and neurologic disease.     

Distortions in rest-activity rhythm in aging relate to white matter hyperintensities

Distortions in the rest–activity rhythm in aging are commonly observed. Neurodegenerative changes of the suprachiasmatic nucleus have been proposed to underlie this disrupted rhythm. However, based on previous studies, it can be proposed that white matter hyperintensities (WMH) may also play a role in the altered rest–activity rhythm in aging. The present study focused on the rest–activity rhythm, as assessed with actigraphy, and WMH in nondemented aging. With regard to the rest–activity rhythm, the interdaily stability (IS), intradaily variability (IV) and the amplitude (AMP) of the rhythm were of interest. The white matter hyperintensities were examined separately for the periventricular (PVH) and deep white matter (DWMH) regions, while distinguishing between the various locations within these regions (e.g. occipital PVH). The results indicated that frontal DWMH related to both IS and AMP. A reduction in the most active 10-h period mediated the relationship between frontal DWMH and AMP. Possible underlying mechanisms of these associations are discussed.     

White matter-associated microglia: New players in brain aging and neurodegenerative diseases

There has been growing interest in brain aging and rejuvenation. It is well known that brain aging is one of the leading causes of neurodegenerative diseases, such as Alzheimer’s disease, but brain aging alone can cause cognitive decline. Microglia are thought to act as ‘conductors’ of white matter aging by modulating diverse glial cells and phagocytosing white matter-derived myelin debris. A recent study identified a specific subpopulation of microglia in the white matter of aged mice, termed white matter-associated microglia (WAM). Additionally, senescent microglia show impaired phagocytic function and altered lipid metabolism, which cause accumulation of lipid metabolites and eventually lead to myelin sheath degeneration. These results suggest that senescent WAM could be pivotal players in axonal loss during brain aging. The aim of this review is to assess the current state of knowledge on brain aging, with an emphasis on the roles of the white matter and microglia, and suggest potential approaches for rejuvenating the aged brain.     

Testing the white matter retrogenesis hypothesis of cognitive aging

The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimer's disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early- and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late-myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging.     

Neurons related to goal-directed motor acts in inferior area 6 of the macaque monkey

Summary A new class of neurons was identified in the rostral part of inferior area 6 in the macaque monkey (Macaca nemestrina). These neurons fire in relation to motor acts which have a particular aim such as reaching, grasping or holding. The same neuron discharges when the animal uses the right hand, the left hand and, frequently, also the mouth. Furthermore most of these neurons specify how the aim can be achieved (e.g. precision grip vs whole hand prehension). Different types of goal-related neurons form a vocabulary of simple motor acts localized in inferior area 6.     

White matter integrity is associated with cerebrospinal fluid markers of Alzheimer's disease in normal adults

We explored whether white matter (WM) integrity in cognitively normal (CN) older adults is associated with cerebrospinal fluid (CSF) markers of Alzheimer's disease pathology. Twenty CN older adults underwent lumbar puncture and magnetic resonance imaging within a few days of each other. Analysis of diffusion tensor imaging data involved a priori region of interest and voxelwise approaches. The region of interest results revealed a positive correlation between CSF measures of amyloid-beta (Aβ₄₂ and Aβ₄₂/p-Tau₁₈₁) and WM integrity in the fornix, a relationship which persisted after controlling for hippocampal volume and fornix volume. Lower WM integrity in the same portion of the fornix was also associated with reduced performance on the Digit Symbol test. Subsequent exploratory voxelwise analyses indicated a positive correlation between CSF Aβ₄₂/p-Tau₁₈₁ and WM integrity in bilateral portions of the fornix, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and in the corpus callosum and left inferior longitudinal fasciculus. Our results link lower WM microstructural integrity in CN older adults with CSF biomarkers of Alzheimer's disease and suggest that this association in the fornix may be independent of volumetric measures.     

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.     

Gray matter density and white matter integrity in pianists' brain: a combined structural and diffusion tensor MRI study

The current study combined structural magnetic resonance imaging (sMRI) and diffusion tensor MRI (DT-MRI) to investigate both gray matter density (GMD) and white matter integrity (WMI) in 18 pianists and 21 age-matched non-musicians. The pianists began their piano training at a mean age of 12. Voxel-based morphometry of the sMRI data showed that the pianists had higher GMD in the left primary sensorimotor cortex and right cerebellum. Voxel-based analysis of the DT-MRI data showed that pianists had higher fractional anisotropy (FA) (indicating higher WMI) in the right posterior limb of the internal capsule. The sMRI and DT-MRI results indicate that both the GMD and WMI of pianists may exhibit movement-related increases during adolescence or even early adulthood compared with non-musicians.     

White matter impairment in heroin addicts undergoing methadone maintenance treatment and prolonged abstinence: a preliminary DTI study

Methadone maintenance treatment (MMT) might cause the impairments of neuropsychological and neurotransmitter function in opioid addicts. Whether long-term MMT could lead to the impairment of white matter (WM) in heroin addiction brain is unclear. This study compared the WM integrity in the bilateral frontal lobe, temporal lobe, splenium and genu of corpus collasum (CC) between MMT patients (n=13), former heroin addicts (n=11) in prolonged abstinence (PA), and healthy control subjects (n=15) using diffusion tensor imaging (DTI). Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and eigenvalues (λ(⊥), λ(||)) were measured. The correlation between DTI measures and accumulated former heroin dose, total methadone consumption, and PA duration were determined. Although the PA subjects showed no difference in DTI measures relative to the controls, the extensive correlations between the former heroin consumption and the DTI measures were noted. The MMT subjects showed a decreased FA values in the left genu, as well as the increased ADC and λ(⊥) values in the left splenium of CC in comparison to the controls. Compared with the PA, the MMT subjects had a significantly increased ADC value in the bilateral splenium of CC. Importantly, the methadone dosage used in the MMT group was correlated with the FA value in the left splenium of CC and in the right frontal lobe. Our preliminary results suggest that methadone plays a role in the impairment of WM integrity in heroin users on long-term MMT and the normalization of WM injury may occur during abstinence.     

Longitudinal assessment of default-mode brain function in aging

Age-related changes in the default-mode network (DMN) have been identified in prior cross-sectional functional magnetic resonance imaging studies. Here, we investigated longitudinal change in DMN activity and connectivity. Cognitively intact participants (aged 49–79 years at baseline) were scanned twice, with a 6-year interval, while performing an episodic memory task interleaved with a passive control condition. Longitudinal analyses showed that the DMN (control condition > memory task) could be reliably identified at both baseline and follow-up. Differences in the magnitude of task-induced deactivation in posterior DMN regions were observed between baseline and follow-up indicating reduced deactivation in these regions with increasing age. Although no overall longitudinal changes in within-network connectivity were found across the whole sample, individual differences in memory change correlated with change in connectivity. Thus, our results show stability of whole-brain DMN topology and functional connectivity over time in healthy older adults, whereas within-region DMN analyses show reduced deactivation between baseline and follow-up. The current findings provide novel insights into DMN functioning that may assist in identifying brain changes in patient populations, as well as characterizing factors that distinguish between normal and pathologic aging.