Associations between white matter microstructure and cognitive performance in old and very old age.
ABSTRACT: Increasing age is associated with deficits in a wide range of cognitive domains as well as with structural brain changes. Recent studies using diffusion tensor imaging (DTI) have shown that microstructural integrity of white matter is associated with cognitive performance in elderly persons, especially on tests that rely on perceptual speed. We used structural equation modeling to investigate associations between white matter microstructure and cognitive functions in a population-based sample of elderly persons (age ? 60 years), free of dementia, stroke, and neurological disorders (n = 253). Participants underwent a magnetic resonance imaging scan, from which mean fractional anisotropy (FA) and mean diffusivity (MD) of seven white matter tracts were quantified. Cognitive functioning was analyzed according to performance in five task domains (perceptual speed, episodic memory, semantic memory, letter fluency, and category fluency). After controlling for age, FA and MD were exclusively related to perceptual speed. When further stratifying the sample into two age groups, the associations were reliable in the old-old (? 78 years) only. This relationship between white matter microstructure and perceptual speed remained significant after excluding persons in a preclinical dementia phase. The observed pattern of results suggests that microstructural white matter integrity may be especially important to perceptual speed among very old adults.
Project description:BACKGROUND:Although associated with dementia and cognitive impairment, microstructural white matter integrity is a rarely used marker of preclinical dementia. OBJECTIVE:We aimed to evaluate the individual and combined effects of multiple markers, with special focus on microstructural white matter integrity, in detecting individuals with increased dementia risk. METHODS:A dementia-free subsample (n?=?212, mean age?=?71.33 years) included in the population-based Swedish National Study on Aging and Care (SNAC-K) underwent magnetic resonance imaging (T1-weighted, fluid-attenuated inversion recovery, diffusion tensor imaging), neuropsychological testing (perceptual speed, episodic memory, semantic memory, letter and category fluency), and genotyping (APOE). Incident dementia was assessed during six years of follow-up. RESULTS:A global model (global cognition, APOE, total brain tissue volume: AUC?=?0.920) rendered the highest predictive value for future dementia. Of the models based on specific markers, white matter integrity of the forceps major tract was included in the most predictive model, in combination with perceptual speed and hippocampal volume (AUC?=?0.911). CONCLUSION:Assessment of microstructural white matter integrity may improve the early detection of dementia, although the added benefit in this study was relatively small.
Project description:Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the ?4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS.To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia.Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78-90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS.APOE was associated with white matter microstructure in 2 out of 14 tracts; ?4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004).Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia.
Project description:BACKGROUND:Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. OBJECTIVE:To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. METHODS:Neuropsychological assessment, genetic testing (apolipoprotein E -APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years. RESULTS:Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOE?4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ?4 allele, hippocampal volume, white matter-hyperintensity volume). CONCLUSION:This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.
Project description:A latent measure of white matter microstructure (g WM) provides a neural basis for information processing speed and intelligence in adults, but the temporal emergence of g WM during human development is unknown. We provide evidence that substantial variance in white matter microstructure is shared across a range of major tracts in the newborn brain. Based on diffusion MRI scans from 145 neonates [gestational age (GA) at birth range 23+2-41+5 weeks], the microstructural properties of eight major white matter tracts were calculated using probabilistic neighborhood tractography. Principal component analyses (PCAs) were carried out on the correlations between the eight tracts, separately for four tract-averaged water diffusion parameters: fractional anisotropy, and mean, radial and axial diffusivities. For all four parameters, PCAs revealed a single latent variable that explained around half of the variance across all eight tracts, and all tracts showed positive loadings. We considered the impact of early environment on general microstructural properties, by comparing term-born infants with preterm infants at term equivalent age. We found significant associations between GA at birth and the latent measure for each water diffusion measure; this effect was most apparent in projection and commissural fibers. These data show that a latent measure of white matter microstructure is present in very early life, well before myelination is widespread. Early exposure to extra-uterine life is associated with altered general properties of white matter microstructure, which could explain the high prevalence of cognitive impairment experienced by children born preterm.
Project description:We compared trajectories of terminal cognitive decline in older Black (n = 3372) and White (n = 1756) persons from a defined population who completed tests of episodic memory and perceptual speed at 3-year intervals for up to 18 years. During a mean of 9.9 years of observation, 1608 Black persons and 902 White persons died. Preterminal decline of episodic memory did not differ by race. Terminal episodic memory decline began earlier in Black persons (mean of 4.3 years before death) than in White persons (mean = 3.9 years) and progressed more slowly. By contrast, terminal decline of perceptual speed began earlier in White persons (mean = 5.0 years) than in Black persons (mean = 4.5 years). Rate of perceptual speed decline was more rapid in White persons than in Black persons in both the preterminal and terminal periods. The results indicate that terminal cognitive decline occurs in Black persons but suggest that the rate of cognitive decline during the terminal period is less rapid in Black persons than in White persons.
Project description:Alcohol Use Disorders (AUD) is associated with negative consequences on global functioning, likely reflecting chronic changes in brain morphology and connectivity. Previous attempts to characterize cognitive impairment in AUD addressed patients' performance in single domains, without considering their cognitive profile as a whole. While altered cognitive performance likely reflects abnormal white-matter microstructural properties, to date no study has directly addressed the relationship between a proxy of patients' cognitive profile and microstructural damage. To fill this gap we aimed to characterize the microstructural damage pattern, and its relationship with cognitive profile, in treatment-seeking AUD patients. Twenty-two AUD patients and 18 healthy controls underwent a multimodal MRI protocol including diffusion tensor imaging (DTI), alongside a comprehensive neurocognitive assessment. We used a principal component analysis (PCA) to identify superordinate components maximally explaining variability in cognitive performance, and whole-brain voxelwise analyses to unveil the neural correlates of AUD patients' cognitive impairment in terms of different white-matter microstructural features, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). PCA revealed a basic executive component, significantly impaired in AUD patients, associated with tasks tapping visuo-motor processing speed, attention and working-memory. Within a widespread pattern of white-matter damage in patients, we found diverse types of relationship linking WM microstructure and executive performance: (i) in the whole sample, we observed a linear relationship involving MD/RD metrics within both 'superficial' white-matter systems mediating connectivity within large-scale brain networks, and deeper systems modulating their reciprocal connections; (ii) in AUD patients vs. controls, a performance-by-group interaction highlighted a MD/AD pattern involving two frontal white-matter systems, including the genu of corpus callosum and cingulum bundle, mediating structural connectivity among central executive, salience and default mode networks. Alterations of prefrontal white-matter pathways are suggestive of abnormal structural connectivity in AUD, whereby a defective interplay among large-scale networks underpins patients' executive dysfunction. These findings highlight different directions for future basic and translational research aiming to tailor novel rehabilitation strategies and assess their functional outcomes.
Project description:Individuals born very preterm (VPT; <32 weeks' gestational age) are at increased risk of impaired mathematics and word reading performance, as well as widespread white matter microstructural alterations compared with individuals born full term (FT; ≥37 weeks' gestational age). To date, the link between academic performance and white matter microstructure is not well understood. This study aimed to investigate the associations between mathematics and reading performance with white matter microstructure in 114 VPT and 36 FT 13-year-old children. Additionally, we aimed to investigate whether the association of mathematics and reading performance with white matter microstructure in VPT children varied as a function of impairment. To do this, we used diffusion tensor imaging and advanced diffusion modelling techniques (Neurite Orientation Dispersion and Density Imaging and the Spherical Mean Technique), combined with a whole-brain analysis approach (Tract-Based Spatial Statistics). Mathematics performance across VPT and FT groups was positively associated with white matter microstructural measurements of fractional anisotropy and neurite density, and negatively associated with radial and mean diffusivities in widespread, bilateral regions. Furthermore, VPT children with a mathematics impairment (>1 standard deviation below FT mean) had significantly reduced neurite density compared with VPT children without an impairment. Reading performance was not significantly associated with any of the white matter microstructure parameters. Additionally, the associations between white matter microstructure and mathematics and reading performance did not differ significantly between VPT and FT groups. Our findings suggest that alterations in white matter microstructure, and more specifically lower neurite density, are associated with poorer mathematics performance in 13-year-old VPT and FT children. More research is required to understand the association between reading performance and white matter microstructure in 13-year-old children.
Project description:Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ?60?y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (? - 1.10 [95% CI - 1.98, - 0.23]), category fluency (? - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (? - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOE?4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.
Project description:<b>Background: </b>Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia.<br><br><b>Objectives: </b>To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60-77 years) from the general population.<br><br><b>Methods: </b>This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n?=?34) or control group (general health advice, n?=?26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed.<br><br><b>Results: </b>FA decreased, and cognition improved more in the intervention group compared to the control group (p?<?0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group.<br><br><b>Conclusion: </b>The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations.
Project description:White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.