CSF Proteomic Profiles Associated With White Matter Integrity in Cognitively Normal Older Adults With and Without Amyloid Pathology.

BackgroundGrowing evidence indicates a potential role of white matter damage in the onset and progression of Alzheimer's disease (AD). Understanding the biological processes underlying in‐vivo white matter imaging biomarkers is essential for broadening their use beyond research settings and identifying new potential targets for disease prevention and modification strategies.MethodsWe selected 96 non‐demented older individuals from the Alzheimer Centrum Amsterdam with available DTI and CSF proteomic data. Fractional anisotropy (FA) and mean diffusivity (MD) values were computed for the total white matter, and for 12 tracts of interest, using tract‐based spatial statistics. We tested associations between protein levels (predictors) and both global FA and MD values (outcomes) with linear models, correcting for age and sex. Models further included an interaction between protein levels and amyloid status. Gene‐set and cell‐type enrichment analysis were performed on proteins showing significant associations.ResultsCSF levels of 234 (17.1%) proteins were associated with global DWI measures (Figure 1). Of these, 70 were unique for FA, and 70 for MD, while the remaining proteins were associated with both measures (WM‐generic proteins). WM‐generic proteins were related to pathways of lipid metabolism and enriched in endothelial cells. FA‐specific proteins were mostly related to blood coagulation pathways and enriched in astrocytes and in neurons. MD‐specific proteins were related to actin filaments and mainly expressed in oligodendrocytes. Testing interaction terms of protein levels with amyloid status (Figure 2), revealed both global FA and MD alterations in amyloid positive participants were associated with biological processes of axonogenesis, synaptic organization and plasticity. Regional analysis revealed distinct proteomic profiles associated with variations in regional FA and MD, with processes linked to synaptic plasticity and axon extension specifically related to limbic and posterior projections fibers (Figure 3).ConclusionsThese results provide new insights into the biological mechanisms underlying white matter integrity and its spatial relationship to AD pathology. The observed amyloid‐dependent associations underscore the interplay between amyloid pathology and white matter damage, suggesting that interventions targeting synaptic organization, axonogenesis, and plasticity may hold promise for mitigating disease progression.

Polymicrogyria (PMG), a neuronal migration disorder, commonly manifests as a seizure disorder. The aim of this study was to look for the abnormalities in the underlying white matter using diffusion tensor imaging (DTI) that appeared normal on conventional magnetic resonance imaging (MRI) in patients with PMG. DTI was performed in three patients with PMG and eight age- and sex-matched healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated for the cortex and adjoining subcortical white matter in both controls and patients. We observed a significantly decreased mean FA value with no significant change in the MD value in subcortical white matter underlying polymicrogyric cortex (FA = 0.23+/-0.04, MD = 1.0+/-0.05 x 10(-3) mm(2)/s) as compared to both contralateral (FA = 0.32+/-0.04, MD = 1.0+/-0.05 x 10(-3) mm(2)/s) and normal control (FA = 0.32+/-0.04, MD = 1.0+/-0.06 x 10(-3) mm(2)/s) white matter. Significantly increased MD and decreased FA values were also observed in the polymicrogyric cortex (FA = 0.08+/-0.01, MD = 1.2+/-0.10 x 10(-3) mm(2)/s) as compared to normal contralateral (FA = 0.12+/-0.04, MD = 1.1+/-0.09 x 10(-3) mm(2)/s) and normal control (FA = 0.12+/-0.01, MD = 1.1+/-0.09 x 10(-3) mm(2)/s) cortex. Significantly decreased FA values with no change in MD values in the subcortical white matter subjacent to polymicrogyric cortex reflect microstructural changes in the white matter probably due to the presence of ectopic neurons.

Background: A decline in cerebral White Matter (WM) integrity occurs across the adult lifespan, with more rapid degradation later in life. Diffusion Tensor Imaging (DTI) is a non-invasive method to evaluate the microscopic changes of WM in vivo. Linear regression models have been applied to depict the relationship between diffusion properties, such as Fractional Anisotropy (FA) and Mean Diffusivity (MD), derived from DTI and age. However, the fit of these linear regression models is unsatisfactory. Objectives: The purpose of our study was to investigate the age-related changes of WM in an elderly population. Methods: We performed statistical parametric mapping with DTI to evaluate the patterns of age-related microscopic WM changes with voxel-based analysis in the elderly population (>55 years old). A linear regression model was used to examine the associations between DTI parameters and age. Results: The fit of the linear regression model depicting the association between mean global FA, MD values (FA, MD derived from global WM), and age was better than that reported in prior studies using DTI (R2=0.4252, p<0.001 for global FA and age; R2=0.5309, p<0.001 for global MD and age). Moreover, comparable to previous studies, the mean global FA showed a significant negative correlation with mean global MD, indicating a true age-related phenomenon of increased interstitial or intracellular fluid accumulation in cerebral WM. The mean frontal FA value was significantly lower than the mean global FA value. However, there was no significant difference between the mean frontal MD value and the mean global MD value. Conclusions: Focusing on the elderly population, we can improve the fit of linear regression models to investigate the age-related changes of WM by DTI. These results suggest that age-related microscopic changes of WM might be occurring more consistently in later life.

Fabry disease (FD), an X‑linked lysosomal disorder caused by deficient α‑galactosidaseA (α-GalA), leads to glycosphingolipid accumulation and multi-organ damage. The specific characteristics and clinical relevance of white matter microstructural damage in FD remain insufficiently explored. This study therefore aimed to explore these specific changes using automated fiber quantification (AFQ), as well as to analyze their correlations with neuropsychological scales and clinical indicators. 19FD patients and 22healthy controls (HC) underwent neuropsychological assessments and diffusion tensor imaging (DTI). The AFQ technique was used to extract fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values at 100 equidistant nodes along 18major white matter tracts. Partial correlation analysis explored relationships between DTI indicators and neuropsychological as well as clinical indicators. ROC analysis was performed to evaluate the diagnostic efficacy of the FA and MD values in differentiating FD patients from HC. FD patients showed decreased FA values and increased MD, AD, and RD values in several fiber tracts, particularly in the corticospinal tract (CST) and the cingulum cingulate (CC). Diffusion metrics in the left CC (CC_L) showed significant correlations with neuropsychological scores: the FA values were positively correlated with the MMSE score, while the MD and RD values were negatively correlated with the MMSE score. Additionally, the MD and RD values were positively correlated with the HAMD and HAMA scores, respectively. The AD values of the left CST (CST_L), as well as the MD and AD values of the left arcuate fasciculus (AF_L), were negatively correlated with α‑galactosidaseA (α-GalA) activity in FD patients. Furthermore, ROC analysis demonstrated that the MD values of the right CST (CST_R) achieved superior diagnostic performance (AUC = 0.933). FD patients demonstrated segment-specific white matter damage. The abnormalities in these specific fiber segments were associated with symptoms such as cognitive impairment and depression, especially in the CC and CST. These findings may provide novel insights into the clinical symptoms associated with FD and offer new neuroimaging support for disease monitoring in this condition.

This study aimed to detect white matter changes and different effects of thyroid hormone on the white matter integrity in young adult male patients with childhood-onset growth hormone deficiency (CO-GHD), compared with healthy people. Magnetic resonance imaging (structural imaging and diffusion tensor imaging) was performed in 17 young adult male patients with CO-GHD and 17 healthy male controls. The white matter volume, mean diffusivity (MD) values and fractional anisotropy (FA) values were quantified and compared between two groups (CO-GHD group vs. control group). We assessed the interaction effects between thyroid hormone and groups (CO-GHD group vs. control group) on white matter integrity. Patients with CO-GHD exhibited similar white matter volumes compared with controls. However, compared with the controls, patients with CO-GHD showed a significant reduction in FA values in six clusters and a substantial increase in MD values in four clusters, mainly involving the corticospinal tracts, corpus callosum and so on. Moreover, after correcting for insulin-like growth factor-1 levels, the significant interaction effects between groups (CO-GHD group vs. control group) and serum free thyroxine levels on MD values were noted in three clusters, mainly involving in superior longitudinal fasciculus and sagittal stratum. In conclusion, young males with CO-GHD showed white matter changes in multiple brain regions and different effects of thyroid hormone on the white matter integrity.

The causes of behavioral and psychological symptoms of dementia (BPSD) vary according to the dementia subtype and associated neuropathology. The present study aimed to (i) compare BPSD between patients with subcortical ischemic vascular disease (SIVD) and Alzheimer’s disease (AD) across stages, and (ii) explore the associations with diffusion tensor imaging (DTI) in the corpus callosum (CC) and other major fibers. Twenty-four patients with SIVD and 32 with AD were recruited. Four domains of the Neuropsychiatric Inventory (NPI) (hyperactivity, psychosis, affective, and apathy) and two DTI parameters [fractional anisotropy (FA) and mean diffusivity (MD)] within the genu, body (BCC), and splenium (SCC) of the CC and other major fibers were assessed. Overall, the patients with clinical dementia rating (CDR) 1 ~ 2 had higher scores in apathy domain than those with CDR0.5. Among those with CDR1 ~ 2, SIVD had higher scores in apathy domain than AD. MD values in the BCC/SCC were positively correlated with total NPI score and psychosis, hyperactivity, and apathy domains. FA values in the SCC were inversely correlated with total NPI score and psychosis domain. The correlations were modified by age, the CASI, and CDR scores. Stepwise linear regression models suggested that FA value within the left superior longitudinal fasciculus predicted the hyperactivity domain. MD value within the SCC/left uncinate fasciculus and FA value within the GCC/left forceps major predicted the psychosis domain. MD value within the right superior longitudinal fasciculus and CDR predicted the apathy domain. Further analysis suggested distinct patterns of regression models between SIVD and AD patients. White matter integrity within the BCC/SCC had associations with multi-domains of BPSD. Our study also identified important roles of regions other than the CC to individual domain of BPSD, including the left superior longitudinal fasciculus to the hyperactivity domain, the left uncinate fasciculus/forceps major to the psychosis domain, and the right superior longitudinal fasciculus to the apathy domain. The neuronal substrates in predicting BPSD were different between SIVD and AD patients. Of note, apathy, which was more profound in SIVD, was associated with corresponding fiber disconnection in line with dementia severity and global cognition decline.

Drug-induced parkinsonism (DIP) is the second most common etiology of parkinsonism. And yet, there is little information on structural imaging in DIP to elucidate the accurate underlying pathomechanisms. To investigate microstructural white matter (WM) in patients with DIP using diffusion tensor image and to determine its relationship to severity of parkinsonian motor symptoms and cognitive function. A total of 42 patients with DIP, 65 with Parkinson's disease, and 33 control subjects were recruited from a movement disorders outpatient clinic. We performed comparative analysis of fractional anisotropy (FA) and mean diffusivity (MD) values among groups using tract-based spatial statistics. Correlation analysis between WM integrity and parkinsonian motor symptoms and cognitive performance was also performed in DIP patients using voxel-wise statistical analysis. DIP patients had significantly lower FA and higher MD values over widespread WM areas than control subjects. The patients with DIP had poor cognitive performance relative to control subjects, which correlated well with WM properties. Additionally, the parkinsonian motor symptoms were negatively correlated with FA values. In contrast, exposure time to the offending drugs prior to the development of parkinsonism or duration of parkinsonism showed no significant association with FA or MD values. The present study demonstrates that disruption of the WM microstructure is extensive in patients with DIP, and it is correlated with clinical parameters of parkinsonism and cognitive performance. This suggests that DIP may be reflective of underlying abnormality of microstructural WM. Hum Brain Mapp 38:6043-6052, 2017. © 2017 Wiley Periodicals, Inc.

Objective Using diffusion tensor imaging (DTI) to explore the microstructure changes of white matter in subcortical ischemic vascular cognitive impairment (SIVCI) and its correlation with cognitive function. Methods Forty-nine patients with subcortical ischemic cerebrovascular diseases were collected. By using Clinical Dementia Rating Scale (CDR), they were classified into 10 cases of vascular dementia (VaD group), 20 cases of vascular cognitive impairment-no dementia (VCIND group) and 19 cases of normal cognitive function (control group). Conventional MRI and DTI were performed in all cases. Based on the DTI data, voxel-based analysis was used to assess the whole brain region. Correlation analysis was applied to illustrate the relationship between DTI parameters and cognitive scale in VaD patients. Results Compared with the control group, fractional anisotropy (FA) values of patients in VaD group decreased in medial prefrontal cortex, anterior cingulate cortex, corpus callosum stem, bilateral parietal lobes, right temporal lobe and bilateral orbitofrontal lobes ( P = 0.000, for all), and FA values of patients in VCIND group decreased in right inferior frontal gyrus, right hippocampus and bilateral precuneus ( P = 0.000, for all). Compared with VCIND group, FA values of patients in VaD group decreased in medial prefrontal cortex, anterior cingulate, corpus callosum, bilateral parietal lobes and right temporal lobe ( P = 0.000, for all). Compared with the control group, mean diffusivity (MD) values in VaD group increased in medial prefrontal cortex, corpus callosum, bilateral parietal lobes, bilateral temporal lobes and anterior cingulate ( P = 0.000, for all), while in VCIND group increased in bilateral precuneus and right hippocampus ( P = 0.000, for all). Compared with VCIND group, MD values in VaD group increased in right medial prefrontal cortex, anterior cingulate cortex, corpus callosum stem, bilateral parietal lobes and bilateral temporal lobes ( P = 0.000, for all). The correlation analysis showed that the FA value of medial prefrontal lobe in VaD group was negatively correlated with the time to finish Trail Making Test A (TMT-A; r = - 0.782, P = 0.007), and MD value of bilateral inferior frontal gyrus was positively correlated with the time to complete TMT-A ( r = 0.877, P = 0.001). Conclusions DTI was more sensitive on the white matter microstructure change of SIVCI patients than conventional MRI. It can reflect patient's early cognitive functional changes. Microstructrual change in medial prefrontal white matter is an important factor which may influence the executive functions of patients with SIVCI. doi: 10.3969/j.issn.1672-6731.2014.04.009

In temporal lobe epilepsy (TLE), the epileptogenic focus is focal and unilateral in the majority of patients. A key characteristic of focal TLE is the presence of subclinical epileptiform activity in both the ictal and contralateral "healthy" hemisphere. Such interictal activity is clinically important, as it may reflect the spread of pathology, potentially leading to secondary epileptogenesis. The role played by white matter pathways in this process is unknown. We compared three interhemispheric white matter tracts (anterior commissure, fornix, and tapetum) to determine the pathway most associated with the presence of contralateral interictal spikes. Forty patients with unilateral left or right TLE were categorized based on the presence or absence of contralateral interictal spikes. Analyses of variance (ANOVAs) were run on diffusion properties from each tract. The analyses revealed that patients with left TLE and with bilateral interictal spikes had lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the tapetum. Patients with right TLE did not show this effect. No significant associations with bilateral activity were observed for the other tracts. Blood oxygen level-dependent (BOLD) functional connectivity data revealed that homotopic lateral, not mesial, temporal areas were reliably correlated in bilateral patients, independent of ictal side. Our results indicate that, among the tracts investigated, only the tapetum was associated with contralateral epileptiform activity, implicating this structure in seizures and possible secondary epileptogenesis. We describe two mechanisms that might explain this association (the interruption of inhibitory signals or the toxic effect of carrying epileptiform signals toward the healthy hemisphere), but also acknowledge other rival factors that may be at work. We also report that patients with TLE with bilateral spikes had increased lateral bitemporal lobe connectivity. Our current results can be seen as bringing together important functional and structural data to elucidate the basis of contralateral interictal activity in focal, unilateral epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Background:Cigarette smoking (CS) is highly comorbid with alcohol use disorder (AUD). Both are associated with lower white matter (WM) integrity, with potentially additive effects. This study is a starting point to determine the individual and combined effects of CS and AUD on WM integrity. Methods:Thirty subjects with varying CS and alcohol use (40.0 ± 12.9 years, 13 females, 17 males) underwent structural (T1-weighted) and diffusion weighted magnetic resonance imaging. Indices of WM integrity, fractional anisotropy (FA) and mean diffusivity (MD), were calculated at a voxel-wise level. Parametric maps of FA and MD were spatially normalized to Montreal Neurological Institute space. Average FA and MD values were extracted for 48 WM tracts from the Johns Hopkins University WM tract atlas. Alcohol drinking and CS were characterized by: DSM-5 AUD symptom checklist, Obsessive Compulsive Drinking Scale (OCDS, including obsessive and compulsive subscales), Timeline Followback (TLFB; drinks/drinking day and drinks/week), Alcohol Use Disorders Identification Test (AUDIT), Fagerstrom Test for Nicotine Dependence (FTND), self-reported pack years, and cigarettes/day. Linear regression was performed between FA and MD with alcohol and CS metrics. Results:We found significant negative correlations (p&lt;0.01) between bilateral cingulate gyri FA and total OCDS score and subscales, drinks/drinking day, drinks/week, and AUDIT. Right inferior cerebellar peduncle FA was negatively correlated with FTND and cigarettes/day. Bilateral superior cerebellar peduncle MD was positively correlated with FTND and cigarettes/day. Left cingulate hippocampus MD was positively correlated with OCDS compulsivity. Conclusion:Alcohol use was negatively correlated with cingulate gyrus WM FA, which is implicated in goal-directed behavior and salience attribution. CS was negatively correlated with cerebellar peduncle FA; however, the interpretation of this is unclear. Our results support the hypothesis that both CS and AUD negatively impact WM integrity. Future work will determine the potentially additive effects of smoking and alcohol use.

Cognition-related white matter integrity dysfunction in Alzheimer's disease with diffusion tensor image

Abnormalities in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and mean diffusivity (MD) values can be used to assess microstructural damage to white matter tracts and could represent a quantitative marker of chronic ischemia and thereby potentially serve as a stroke risk factor or a measure of existing subclinical ischemic disease burden. We performed a systematic review and 3 separate meta-analyses to evaluate the association between unilateral carotid steno-occlusion and ipsilateral ADC, FA, or MD abnormality. A comprehensive literature search evaluating the association of carotid disease and quantitative white matter diffusion imaging was performed. The included studies examined patients for ADC, FA, and MD values ipsilateral and contralateral to the site of carotid artery disease. Three meta-analyses using standardized mean differences with assessment of study heterogeneity were performed. Of the 2,920 manuscripts screened, 6 met eligibility for meta-analysis. Of the included manuscripts, 2 studied ADC values, 6 studied FA values, and 2 studied MD values. Our 3 meta-analyses showed standardized mean difference for ADC, FA, and MD values between cerebral hemispheres ipsilateral and contralateral to carotid artery disease site as 1.13 (95% CI: .79-1.47, P < .001), -.42 (95% CI: -.62 to -.21, P < .001), and .23 (95% CI: -.32 to -.77, P = .41), respectively. Measures of heterogeneity showed mild heterogeneity in the 3 meta-analyses. Carotid artery disease is associated with significant ADC and FA value changes, suggesting that carotid disease is associated with quantifiable white matter microstructural damage.

Diffusion tensor imaging has been useful in demonstrating non-decussating corticospinal tract (CST) and superior cerebellar peduncles (SCP) in Joubert syndrome (JS) related disorder and in horizontal gaze palsy with progressive scoliosis (HGPPS). However, measurements of fractional anisotropy (FA) and mean diffusivity (MD) have never been performed in these diseases. The aim of our work was to investigate if FA and MD values in uncrossed white matter bundles due to defective axon guidance are different from normal decussating fibers. Two patients with HGPPS and four with JS were included. FA and MD were measured by region of interest manually placed on the CST, the SCP and the posterior rows (PR) of the pons. The same measurements were performed in 59 control patients. Comparison of these values between patients and controls was performed by graphical inspection. MD values were normal in all cases. In all patients with HGPPS and JS, FA measurements in SCP were not different from normal controls. FA values in PR and in CST were not different in JS patients but higher than in controls in HGPPS patients. This difference was statistically significant. Normal MD values seem to indicate that MD and FA values likely represent two very different processes in the developing brain. High FA values in PRs and CST in HGPPS, implicating micro- scopic deficits of axonal structures, is a unique finding in this disease. Abnormal measurements on PR confirm a role of these fibers in the pathogenesis and clinical presentation of HGPPS.

Diffusion tensor imaging measures of normal appearing white matter in patients who are aging, or have amnestic mild cognitive impairment, or Alzheimer’s disease

Introduction: {Human Immunodeficiency Virus (HIV)-associated Neurocognitive Disorder (HAND)} affects the everyday functioning of patients. It is usually difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing, such as the International HIV Dementia Scale (IHDS), is required. Neuroimaging techniques hold great promise in the early diagnosis and management of HAND, but there is a paucity of studies on the evaluation of HAND using Diffusion Tensor Imaging (DTI) in the Indian population. Aim: To investigate DTI and interpret Fractional Anisotropy (FA) and Mean Diffusivity (MD) values in the White Matter (WM) of patients with HAND and compare them with age and sex- matched controls. Materials and Methods: A case-control study was conducted at the Department of Radiodiagnosis, ABVIMS and Dr. RML Hospital, New Delhi, India, from January 2021 to May 2022. Thirty subjects (15 cases and 15 controls) were included. HIV-positive patients underwent the IHDS to assess cognitive impairment. Magnetic Resonance Imaging (MRI) examination was performed at three tesla using conventional sequences, and DTI was applied. Maps of FA and MD values were generated. Mean FA and MD values of normal-appearing white matter tracts between cases and controls were compared using a t-test. Spearman's correlation test was applied to assess the correlation between IHDS scores and DTI parameters. Results: The majority of cases in the study were in the age group of 31-40 years, and the mean age of cases was 41.27±11.16 years. The present study revealed significantly lower FA values compared to controls in bilateral Frontal WM, Parieto-occipital WM, genu of the Corpus Callosum (CC), right hippocampal WM, and right corona radiata. The mean MD of bilateral Frontal WM, Parieto-occipital WM, corona radiata, and Hippocampal WM was significantly increased in cases compared to healthy controls. A significant association was found between the IHDS score and FA values of the genu of the CC (rho= 0.7), right corona radiata (rho= 0.7), right Hippocampal WM (rho= 0.9), and MD of the left Parieto-occipital WM (rho= -0.6), and left hippocampal WM (rho= -0.5). Conclusion: Diffusion tensor MR imaging can detect abnormalities that are missed by routine MR imaging. DTI provides a valuable marker to monitor HIV-associated Central Nervous System (CNS) injury, which can lead to neurocognitive impairment.