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.     

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.     

Abnormal white matter independent of hippocampal atrophy in amnestic type mild cognitive impairment

Hippocampal atrophy is the key marker in the pathogenesis of Alzheimer's disease (AD), which is associated with white matter (WM) disruption. This type of WM disruption could partly explain AD-related pathology. However, relatively little attention has been directed toward WM disruption which may be independent of these fundamental gray matter (GM) changes in amnestic mild cognitive impairment (aMCI) which is associated with high risk of AD. To evaluate the differences of WM integrity between aMCI patients (N = 32) and healthy controls (N = 31), whole-brain voxel-based methods were applied to diffusion tensor imaging. To explore the possible independence of WM changes from GM loss, an index of hippocampal atrophy was used to partial out GM effects. aMCI patients showed WM disruption in frontal lobe, temporal lobe, internal capsule, cingulate gyrus and precuneus. The findings supported the evidence of independent patterns of degeneration in WM tracts which may co-act in the WM pathological process of aMCI patients. As aMCI is a putatively prodromal syndrome to AD, these data may assist with a better understanding of WM pathological change associated with the development of AD.     

Verbal fluency performance in amnestic MCI and older adults with cognitive complaints

Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimer's disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n = 37), cognitive complaints (CC, n = 37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n = 33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes.     

A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.     

rs-fMRI、DTI及1H-MRS在阿尔茨海默病中的应用进展

随着磁共振成像技术的飞速发展,对阿尔茨海默病的神经影像学研究也越来越深入。其主要目的是通过磁共振影像学特征来识别出早期阿尔茨海默病患者,从而达到早期诊断和治疗的目的。本文就磁共振成像技术包括静息态功能磁共振成像、弥散张量成像及磁共振波谱在阿尔茨海默病的应用进展进行综述。     

Structural and functional neural correlates of visuospatial information processing in normal aging and amnestic mild cognitive impairment

Our understanding of cognitive changes related to human aging and their underlying neural processes is challenged by the distinction between normal and pathological aging. In our study, the neural correlates of visuospatial working memory (VSWM) in young persons (YC), healthy older adults (HC) and patients with amnestic mild cognitive impairment (aMCI) were investigated. Effects of the genetic risk factor apolipoprotein E (ApoE) ε4 on a VSWM task were analyzed for HC and aMCI patients. Higher cortical activation in extrastriate occipital regions and significantly decreased brain volumes in frontoparietal areas were observed in HC compared with young persons. Also, reduced cortical activation in the right middle frontal gyrus and superior frontal gyrus was observed in aMCI-patients compared with HC. Thus, attenuated cortical activation during VSWM tasks is related to the formation of aMCI and may serve as an early marker for cognitive decline. In contrast to previous studies, no significant apolipoprotein E-linked differences were found between HC and aMCI groups.     

Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer's disease and mild cognitive impairment

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.     

Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification

Magnetic resonance imaging (MRI) patterns were examined together with cerebrospinal fluid (CSF) biomarkers in serial scans of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with mild cognitive impairment (MCI). The SPARE-AD score, summarizing brain atrophy patterns, was tested as a predictor of short-term conversion to Alzheimer's disease (AD). MCI individuals that converted to AD (MCI-C) had mostly positive baseline SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD) and atrophy in temporal lobe gray matter (GM) and white matter (WM), posterior cingulate/precuneous, and insula. MCI individuals that converted to AD had mostly AD-like baseline CSF biomarkers. MCI nonconverters (MCI-NC) had mixed baseline SPARE-AD and CSF values, suggesting that some MCI-NC subjects may later convert. Those MCI-NC with most negative baseline SPARE-AD scores (normal brain structure) had significantly higher baseline Mini Mental State Examination (MMSE) scores (28.67) than others, and relatively low annual rate of Mini Mental State Examination decrease (−0.25). MCI-NC with midlevel baseline SPARE-AD displayed faster annual rates of SPARE-AD increase (indicating progressing atrophy). SPARE-AD and CSF combination improved prediction over individual values. In summary, both SPARE-AD and CSF biomarkers showed high baseline sensitivity, however, many MCI-NC had abnormal baseline SPARE-AD and CSF biomarkers. Longer follow-up will elucidate the specificity of baseline measurements.     

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 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.     

MCI patients’ EEGs show group differences between those who progress and those who do not progress to AD

The theta/gamma and alpha3/alpha2 ratio were investigated as early markers for prognosticating of progression to dementia. 76 subjects with mild cognitive impairment (MCI) underwent EEG recording, MRI scans and neuropsychological (NPS) tests. After 3 years of follow-up, three subgroups were characterized as converters to Alzheimer's disease (AD, N = 18), converters to non-AD dementia (N = 14) and non-converters (N = 44). The theta/gamma and alpha3/alpha2 ratio, performance on cognitive tests and hippocampal volume, as evaluated at the time of initial MCI diagnosis, were studied in the three groups. As expected, MCI to AD converters had the smallest mean hippocampal volume and poorest performance on verbal learning tests, whereas MCI to non-AD converters had poorest cognitive performance in non-verbal learning tests, abstract thinking, and letter fluency. Increased theta/gamma ratio was associated with conversion to both AD and non-AD dementia; increased alpha3/alpha2 ratio was only associated with conversion to AD.Theta/gamma and alpha3/alpha2 ratio could be promising prognostic markers in MCI patients. In particular, the increase of high alpha frequency seems to be associated with conversion in AD. EEG markers allow a mean correct percentage of correct classification up to 88.3%. Future prospective studies are needed to evaluate the sensitivity and specificity of these measures for predicting an AD outcome.     

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.     

A structural equation modeling investigation of age-related variance in executive function and DTI measured white matter damage

Cognitive changes in normal aging have been explained by the frontal-executive hypothesis, but the assumptions made by this hypothesis concerning the neurobiological causes are still a matter of debate. Executive functions (EF) may activate neural networks that include disparate grey matter regions, and rely on the integrity of white matter connections. In 118 adults (50–90 years old) from the GENIE study, white matter integrity was measured using diffusion tensor imaging, and information processing speed, fluid intelligence and EF were assessed. A theory-driven structural equation model was developed to test associations between variables. The model was revised, removing non-significant paths. The adjusted model explained well the covariance in our data; and suggested that the reduction in white matter integrity associated with age directly affected only working memory. Fluid intelligence was mediated by all measured cognitive variables. The results suggest that white matter integrity may be particularly important for abilities activating complex neural networks, as occurs in working memory. Integration of the information processing speed and frontal-executive hypotheses may provide important information regarding common, unique, and mediating factors in cognitive aging.     

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.     

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.     

Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment

Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic.Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n = 39) and SCI (n = 8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers.Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimer's disease (AD).     

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI

Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.