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Abstract

Alzheimer's disease is increasingly considered a large-scale network disconnection syndrome, associated with progressive aggregation of pathological proteins, cortical atrophy, and functional disconnections between brain regions. These pathological changes are posited to arise in a stereotypical spatiotemporal manner, targeting intrinsic networks in the brain, most notably the default mode network. While this network-specific disruption has been thoroughly studied with functional neuroimaging, changes to specific white matter fibre pathways within the brain's structural networks have not been closely investigated, largely due to the challenges of modelling complex white matter structure. Here, we applied a novel technique known as 'fixel-based analysis' to comprehensively investigate fibre tract-specific differences at a within-voxel level (called 'fixels') to assess potential axonal loss in subjects with Alzheimer's disease and mild cognitive impairment. We hypothesized that patients with Alzheimer's disease would exhibit extensive degeneration across key fibre pathways connecting default network nodes, while patients with mild cognitive impairment would exhibit selective degeneration within fibre pathways connecting regions previously identified as functionally implicated early in Alzheimer's disease. Diffusion MRI data from Alzheimer's disease (n = 49), mild cognitive impairment (n = 33), and healthy elderly control subjects (n = 95) were obtained from the Australian Imaging, Biomarkers and Lifestyle study of ageing. We assessed microstructural differences in fibre density, and macrostructural differences in fibre bundle morphology using fixel-based analysis. Whole-brain analysis was performed to compare groups across all white matter fixels. Subsequently, we performed a tract of interest analysis comparing fibre density and cross-section across 11 selected white matter tracts, to investigate potentially subtle degeneration within fibre pathways in mild cognitive impairment, initially by clinical diagnosis alone, and then by including amyloid status (i.e. a positive or negative amyloid PET scan). Our whole-brain analysis revealed significant white matter loss manifesting both microstructurally and macrostructurally in Alzheimer's disease patients, evident in specific fibre pathways associated with default mode network nodes. Reductions in fibre density and cross-section in mild cognitive impairment patients were only exhibited within the posterior cingulum when statistical analyses were limited to tracts of interest. Interestingly, these degenerative changes did not appear to be associated with high amyloid accumulation, given that amyloid-negative, but not positive, mild cognitive impairment subjects exhibited subtle focal left posterior cingulum deficits. The findings of this study demonstrated a stereotypical distribution of white matter degeneration in patients with Alzheimer's disease, which was in line with canonical findings from other imaging modalities, and with a network-based conceptualization of the disease.

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... White matter fiber density is reduced in several white matter pathways connecting the frontal, parietal and temporal lobes in AD and MCI (Mito et al., 2018;Roy et al., 2021). ...
... Functional changes observed in the present study could also be linked to changes in structural connectivity, i.e. the increase of fiber density in the kMCT group. Indeed, the structural basis of network disconnection theories of AD proposes that functional disconnections are likely to be mediated by disruption of white matter fiber pathways, propagating pathology across networks (Mito et al., 2018). An increase of fixel-based apparent fiber density could indicate "strengthened" axons, i.e. more cylindrical, less swollen and a less dystrophic shape, mediated by perhaps thicker myelin sheaths after the ketogenic intervention. ...
... This may be attributed to the fact that the extent of white matter connections analyzed was larger in the present study, in which we averaged connections of the whole DAN. In our previous report, smaller and different white matter fascicles were extracted and evaluated, such as the fornix, uncinate and cingulum, which are commonly reported to undergo microstructural alterations in AD (Mito et al., 2018;Roy et al., 2020). ...
Article
Ketones, the brain's alternative fuel to glucose, bypass the brain glucose deficit and improve cognition in mild cognitive impairment (MCI). Our goal was to assess the impact of a 6-month ketogenic intervention on the functional connectivity within eight major brain resting-state networks, and its possible relationship to improved cognitive outcomes in the BENEFIC trial. MCI participants were randomized to a placebo (n= 15) or ketogenic medium chain triglyceride (kMCT; n= 17) intervention. kMCT was associated with increased functional connectivity within the dorsal attention network (DAN), which correlated to improvement in cognitive tests targeting attention. Ketone uptake (¹¹C-acetoacetate PET) specifically in DAN cortical regions was highly increased in the kMCT group and was directly associated with the improved DAN functional connectivity. Analysis of the structural connectome revealed increased fiber density within the DAN following kMCT. Our findings suggest that ketones in MCI may prove beneficial for cognition at least in part because they improve brain network energy status, functional connectivity and axonal integrity.
... By examining both PET and dMRI invivo, tau-related white matter alterations were also reported in studies based on diffusion tensor imaging (DTI) (Jacobs et al., 2018;Wen et al., 2021). Among the affected white matter pathways in Alzheimer's disease, DTI findings showed that long association fibres connecting distant brain regions were mostly impacted (Mito et al., 2018). Similarly, studies on human post-mortem tissue reported associations between white matter degeneration and pathological changes in Alzheimer's disease (McAleese et al., 2017). ...
... CONN-NLM effectively brings further non-local information into the denoising process. CONN-NLM exploits the highly associated information that can be present in dMRI and PET data (McAleese et al., 2017;Jacobs et al., 2018;Mito et al., 2018;Wen et al., 2021), to provide a new means to synergise the structural connectivity from dMRI and the molecular imaging information from PET. Specifically, the proposed filter smooths across grey matter regions that are structurally connected via white matter tracts. ...
... Tau-PET data and dMRI data in Alzheimer's disease were used to demonstrate the effectiveness of this method since there is a strong correlation between tau distribution and WM pathways (McAleese et al., 2017;Jacobs et al., 2018;Mito et al., 2018;Bischof et al., 2019;Wen et al., 2021). The white matter bundles in the brain might connect lesions in distant parts of the brain, thus introducing extra connectivity-informed contributions to the non-local PET filtering. ...
Article
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Background Advancements in hybrid positron emission tomography-magnetic resonance (PET-MR) systems allow for combining the advantages of each modality. Integrating information from MRI and PET can be valuable for diagnosing and treating neurological disorders. However, combining diffusion MRI (dMRI) and PET data, which provide highly complementary information, has rarely been exploited in image post-processing. dMRI has the ability to investigate the white matter pathways of the brain through fibre tractography, which enables comprehensive mapping of the brain connection networks (the “connectome”). Novel methods are required to combine information present in the connectome and PET to increase the full potential of PET-MRI. Methods We developed a CONNectome-based Non-Local Means (CONN-NLM) filter to exploit synergies between dMRI-derived structural connectivity and PET intensity information to denoise PET images. PET-MR data are parcelled into a number of regions based on a brain atlas, and the inter-regional structural connectivity is calculated based on dMRI fibre-tracking. The CONN-NLM filter is then implemented as a post-reconstruction filter by combining the nonlocal means filter and a connectivity-based cortical smoothing. The effect of this approach is to weight voxels with similar PET intensity and highly connected voxels higher when computing the weighted-average to perform more informative denoising. The proposed method was first evaluated using a novel computer phantom framework to simulate realistic hybrid PET-MR images with different lesion scenarios. CONN-NLM was further assessed with clinical dMRI and tau PET examples. Results The results showed that CONN-NLM has the capacity to improve the overall PET image quality by reducing noise while preserving lesion contrasts, and it outperformed a range of filters that did not use dMRI information. The simulations demonstrate that CONN-NLM can handle various lesion contrasts consistently, as well as lesions with different levels of inter-connectivity. Conclusion CONN-NLM has unique advantages of providing more informative and accurate PET smoothing by adding complementary structural connectivity information from dMRI, representing a new avenue to exploit synergies between MRI and PET.
... For the single-shell TrackON-HD data, white matter-like fibre orientation distributions (FODs) as well as grey matter-like and CSF-like compartments in all voxels were then computed using Single-Shell 3-Tissue CSD , whilst multi-shell multi-tissue CSD (Jeurissen et al., 2014) was utilised for the TrackON-HD multishell and HD-YAS data. Spatial correspondence was achieved by generating a group-specific population template with an iterative registration and averaging approach using white matter FOD images for 40 subjects (20 preHD and 20 controls, selected at random), in keeping with previous studies (Mito et al., 2018). Each subject's FOD image was then registered to the template via a FOD-guided non-linear registration (Raffelt et al., 2011). ...
... Recent evidence has suggested that the HD mutation may lead to abnormalities in striatal and cortical development (Barnat et al., 2020). Our findings indicate that there is no detectable developmental abnormality in the microstructure of corticostriatal and cortico-thalamic white matter tracts in preHD, using novel fixel-based dMRI analysis, which has been shown to be more sensitive to neurodegeneration of white matter in Alzheimer's disease (Mito et al., 2018) when compared to standard diffusion tensor imaging (DTI) approaches. ...
Article
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Objectives To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington’s disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. Methods We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. Results We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington’s disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. Conclusions Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.
... Older diffusion tensor imaging (DTI) techniques, although historically invaluable in offering the earliest opportunities to non-invasively investigate some microstructural properties of WM and their alteration in aging and disease, suffered from the inability to resolve crossing fibres. It was shown that traditional DTI may lead to artefactual findings in neurodegenerative disorders (Mito et al., 2018;Tournier et al., 2008), both false positive and false negative. This severely limits the extent to which such DTI findings can be interpreted or even safely relied upon. ...
... FD is considered a measure of WM microstructure, while FC is related to macroscopic fibre bundle morphometric change. Although these measures are typically not independent, they can provide insight on different types of WM impairment and have successfully been applied to Alzheimer's disease (Mito et al., 2018). In the context of FTD, we found that both FD and FC were reduced in similar WM regions, which suggest that both fibre atrophy and axonal depletion that are part of the disease. ...
Article
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Recent studies suggest a framework where white matter (WM) atrophy plays an important role in fronto-temporal dementia (FTD) pathophysiology. However, these studies often overlook the fact that WM tracts bridging different brain regions may have different vulnerabilities to the disease and the relative contribution of GM atrophy to this WM model, resulting in a less comprehensive understanding of the relationship between clinical symptoms and pathology. Using a common factor analysis to extract a semantic and an executive factor, we aimed to test the relative contribution of WM and GM of specific tracts in predicting cognition in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). We found that semantic symptoms were mainly dependent on short-range WM fiber disruption, while damage to long-range WM fibers was preferentially associated to executive dysfunction with the GM contribution to cognition being predominant for local processing. These results support the importance of the disruption of specific WM tracts to the core cognitive symptoms associated with FTD. As large-scale WM tracts, which are particularly vulnerable to vascular disease, were highly associated with executive dysfunction, our findings highlight the importance of controlling for risk factors associated with deep white matter disease, such as vascular risk factors, in patients with FTD in order not to potentiate underlying executive dysfunction.
... The FiCD value enables estimation of both the axonal density of all associated fibers connected to a CU and the FA value of each associated fiber. Thus, the decrease in FiCD value may result from the loss of axons leading to atrophy of a fiber bundle across its entire cross-section of a CU (Mito et al., 2018). Another likely scenario is that reduced integrity of the WM is associated with decreased FA values (Alexander et al., 2007). ...
... This finding may be related to axon degeneration and WM demyelination. On the one hand, atrophy of a fiber bundle may indicate a reduction in the space occupied by fiber bundles, leading to changes in macroscopic structure and morphology, such as a decreased cortical thickness and GM volume (Mito et al., 2018). On the other hand, the speed and capacity of information transmission between a pair of cortical regions connected by a damaged fiber bundle may be reduced. ...
Article
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Abnormal brain structural connectivity of end-stage renal disease(ESRD) is associated with cognitive impairment. However, the characteristics of cortical structural connectivity have not been investigated in ESRD patients. Here, we study structural connectivity of the entire cerebral cortex using a fiber connectivity density(FiCD) mapping method derived from diffusion tensor imaging(DTI) data of 25 ESRD patients and 20 healthy controls, and between-group differences were compared in a vertexwise manner. We also investigated the associations between these abnormal cortical connectivities and the clinical variables using Pearson correlation analysis and multifactor linear regression analysis. Our results demonstrated that the mean global FiCD value was significantly decreased in ESRD patients. Notably, FiCD values were significantly changed(decreased or increased) in certain cortical regions, which mainly involved the bilateral dorsolateral prefrontal cortex(DLPFC), inferior parietal cortex, lateral temporal cortex and middle occipital cortex. In ESRD patients, we found a trend of negative correlation between the increased FiCD values of bilateral middle frontal gyrus and serum creatinine, urea, parathyroid hormone(PTH) levels and dialysis duration. Only the white matter hyperintensity(WMH) scores were significantly negatively correlated with the global FiCD value in multifactor regression analysis. Our results suggested that ESRD patients exhibited extensive impaired cortical structural connectivity, which was related to the severity of WMHs. A compensation mechanism of cortical structural recombination may play a role in how the brain adapts to maintain optimal network function. Additionally, the serum creatinine, urea and PTH levels may be risk factors for brain structural network decompensation in ESRD patients.
... Previous research has shown that changes in white matter during MCI mainly manifest in variations in MD (Yu et al. 2017). FA variations do not become significant until the onset of AD (Mito et al. 2018). Figure 1 and Supplementary Figure 3 demonstrate that MD is superior to FA in reflecting variations in white matter in the fiber tracts of patients with MCI. ...
... Secondly, classifiers with MD indexes as feature sets have high separability (Fig. 3) in 14 fiber tracts, whereas classifiers with FA indexes as feature sets are all at the random level ( Supplementary Fig. 4). Thirdly, research has shown the sensitivity of the MD index to MCI (Yu et al. 2017) and that FA only begins to have statistical differences in multiple fiber tracts during AD (Mito et al. 2018). Our experiments confirmed the perspectives by statistical differences and classification. ...
Article
Early diagnosis of mild cognitive impairment (MCI) fascinates screening high-risk Alzheimer’s disease (AD). White matter is found to degenerate earlier than gray matter and functional connectivity during MCI. Although studies reveal white matter degenerates in the limbic system for MCI, how other white matter degenerates during MCI remains unclear. In our method, regions of interest with a high level of resting-state functional connectivity with hippocampus were selected as seeds to track fibers based on diffusion tensor imaging (DTI). In this way, hippocampus-temporal and thalamus-related fibers were selected, and each fiber’s DTI parameters were extracted. Then, statistical analysis, machine learning classification, and Pearson’s correlations with behavior scores were performed between MCI and normal control (NC) groups. Results show that: 1) the mean diffusivity of hippocampus-temporal and thalamus-related fibers are significantly higher in MCI and could be used to classify 2 groups effectively. 2) Compared with normal fibers, the degenerated fibers detected by the DTI indexes, especially for hippocampus-temporal fibers, have shown significantly higher correlations with cognitive scores. 3) Compared with the hippocampus-temporal fibers, thalamus-related fibers have shown significantly higher correlations with depression scores within MCI. Our results provide novel biomarkers for the early diagnoses of AD.
... Cerebrovascular pathology and Alzheimer's disease (AD) are intertwined in several respects, as both share common risk factors (Duron and Hanon, 2008) and often overlap and co-occur (Toledo et al., 2013). Furthermore, the risk for developing AD is increased by vascular diseases and elevated WMH (Breteler, 2000;Wolf et al., 2000;Prins et al., 2004), whereas AD patients exhibit elevated levels of cerebral WM pathology (Brickman, 2013) as well as degeneration in specific WM tracts (Mito et al., 2018). Thus, it is of critical importance to study the effects of WM pathology on cognition in AD as well as in mild cognitive impairment (MCI), which is often an early stage of AD. ...
... Thus, it is of critical importance to study the effects of WM pathology on cognition in AD as well as in mild cognitive impairment (MCI), which is often an early stage of AD. However, the topic has received considerably less attention than the association between gray matter morphology and cognition (for exceptions, see Brickman et al., 2008;Brickman, 2013;Ramirez et al., 2014;Bilello et al., 2015;Mito et al., 2018;Kaskikallio et al., 2019a,b). ...
... For example, studies using FBA in healthy adults reported widespread agerelated decreases in FD, FC, and FDC indicative of WM degradation with age [12,13]. Changes in fixel-based metrics have also been observed in neurodegenerative diseases, such as Alzheimer's disease [14] and Parkinson's disease [15e18]. The present study used FBA to assess the effect of MetS on the WM fiberspecific microstructure in older adults and its relationship with MetSrelated measurements and cognitive and locomotor functions to better understand the pathophysiology of MetS. ...
... In accordance with the study by Sala et al. [75], we were unable to demonstrate WM microstructural changes in individuals with preMetS using DTI. This may indicate that fixel-based metrics have a higher sensitivity than DTI in detecting early axon changes, as was also shown previously in studies in neurodegenerative diseases, such as Alzheimer's disease [14], Parkinson's disease [15,18], and multiple sclerosis [48] This fixel-based approach allows us to differentiate between changes in microstructural FD and macrostructural FC; thus, provides greater sensitivity in detecting groupwise differences in preMetS, particularly in crossing fiber regions. ...
Article
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Introduction: Metabolic syndrome (MetS) is defined as a complex of interrelated risk factors for type 2 diabetes and cardiovascular disease, including glucose intolerance, abdominal obesity, hypertension, and dyslipidemia. Studies using diffusion tensor imaging (DTI) have reported white matter (WM) microstructural abnormalities in MetS. However, interpretation of DTI metrics is limited primarily due to the challenges of modeling complex WM structures. The present study used fixel-based analysis (FBA) to assess the effect of MetS on the fiber tract-specific WM microstructure in older adults and its relationship with MetS-related measurements and cognitive and locomotor functions to better understand the pathophysiology of MetS. Methods: Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross-sectional size (FC), and a combination of FD and FC (FDC), were evaluated in 16 healthy controls (no components of metabolic syndrome; four men; mean age, 71.31 ± 5.06 years), 57 individuals with premetabolic syndrome (preMetS; one or two components of MetS; 29 men; mean age, 72.44 ± 5.82 years), and 46 individuals with MetS (three to five components of MetS; 27 men; mean age, 72.15 ± 4.97 years) using whole-brain exploratory FBA. Tract of interest (TOI) analysis was then performed using TractSeg across 14 selected WM tracts previously associated with MetS. The associations between fixel-based metrics and MetS-related measurements, neuropsychological, and locomotor function tests were also analyzed in individuals with preMetS and MetS combined. In addition, tensor-based metrics (i.e., fractional anisotropy [FA] and mean diffusivity [MD]) were compared among the groups using tract-based spatial statistics (TBSS) analysis. Results: In whole-brain FBA, individuals with MetS showed significantly lower FD, FC, and FDC compared with healthy controls in WM areas, such as the splenium of the corpus callosum (CC), corticospinal tract (CST), middle cerebellar peduncle (MCP), and superior cerebellar peduncle (SCP). Meanwhile, in fixel-based TOI, significantly reduced FD was observed in individuals with preMetS and MetS in the anterior thalamic radiation, CST, SCP, and splenium of the CC compared with healthy controls, with relatively greater effect sizes observed in individuals with MetS. Compared with healthy controls, significantly reduced FC and FDC were only demonstrated in individuals with MetS, including regions with loss of FD, inferior cerebellar peduncle, inferior fronto-occipital fasciculus, MCP, and superior longitudinal fasciculus part I. Furthermore, negative correlations were observed between FD and Brinkman index of cigarette consumption cumulative amount and between FC or FDC and the Trail Making Test (parts B-A), which is a measure of executive function, waist circumference, or low-density lipoprotein cholesterol. Finally, TBSS analysis revealed that FA and MD were not significantly different among all groups. Conclusions: The FBA results demonstrate that substantial axonal loss and atrophy in individuals with MetS and early axonal loss without fiber-bundle morphological changes in those with preMetS within the WM tracts are crucial to cognitive and motor function. FBA also clarified the association between executive dysfunction, abdominal obesity, hyper-low-density lipoprotein cholesterolemia, smoking habit, and compromised WM neural tissue microstructure in MetS.
... The state-of-the-art fixel-based analysis, or FBA [10], provides the fiber tract-specific analysis to estimate the quantitative metrics associated with a single fiber population within a voxel (called "fixel"), as opposed to analyses of voxel-averaged metrics. FBA has been shown to be more sensitive and interpretable than voxel-wise methods [11,12], in terms of better reflection of the local microscopic fiber densities. It also accounts for macroscopic morphometric alterations of fiber bundles such as the overall size in the transverse section, known as fixelbased morphometry [12]. ...
... The capability of FBA to quantify fiber-specific measures of micro-/macrostructural alterations has been shown to be more beneficial for cerebral WM over VBA [11,101]. Advancing previous findings based on the DTI model [21,22] and advanced model of structural T1 image [99], our study reveals that the cerebellum and the WM underneath as well as the GM-WM junction at the DLPFC are involved in ASD pathology and associated cognition. ...
Article
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Background Neuroimage literature of autism spectrum disorder (ASD) has a moderate-to-high risk of bias, partially because those combined with intellectual impairment (II) and/or minimally verbal (MV) status are generally ignored. We aimed to provide more comprehensive insights into white matter alterations of ASD, inclusive of individuals with II (ASD-II-Only) or MV expression (ASD-MV). Methods Sixty-five participants with ASD (ASD-Whole; 16.6 ± 5.9 years; comprising 34 intellectually able youth, ASD-IA, and 31 intellectually impaired youth, ASD-II, including 24 ASD-II-Only plus 7 ASD-MV) and 38 demographic-matched typically developing controls (TDC; 17.3 ± 5.6 years) were scanned in accelerated diffusion-weighted MRI. Fixel-based analysis was undertaken to investigate the categorical differences in fiber density (FD), fiber cross section (FC), and a combined index (FDC), and brain symptom/cognition associations. Results ASD-Whole had reduced FD in the anterior and posterior corpus callosum and left cerebellum Crus I, and smaller FDC in right cerebellum Crus II, compared to TDC. ASD-IA, relative to TDC, had no significant discrepancies, while ASD-II showed almost identical alterations to those from ASD-Whole vs. TDC. ASD-II-Only had greater FD/FDC in the isthmus splenium of callosum than ASD-MV. Autistic severity negatively correlated with FC in right Crus I. Nonverbal full-scale IQ positively correlated with FC/FDC in cerebellum VI. FD/FDC of the right dorsolateral prefrontal cortex showed a diagnosis-by-executive function interaction. Limitations We could not preclude the potential effects of age and sex from the ASD cohort, although statistical tests suggested that these factors were not influential. Our results could be confounded by variable psychiatric comorbidities and psychotropic medication uses in our ASD participants recruited from outpatient clinics, which is nevertheless closer to a real-world presentation of ASD. The outcomes related to ASD-MV were considered preliminaries due to the small sample size within this subgroup. Finally, our study design did not include intellectual impairment-only participants without ASD to disentangle the mixture of autistic and intellectual symptoms. Conclusions ASD-associated white matter alterations appear driven by individuals with II and potentially further by MV. Results suggest that changes in the corpus callosum and cerebellum are key for psychopathology and cognition associated with ASD. Our work highlights an essential to include understudied subpopulations on the spectrum in research.
... Under non-pathological conditions, the so-called resting state microglia are characterized by highly ramified processes and a small rounded soma, together with the gene expression of homeostatic microglial markers, such as P2ry12, Tmem119, and Sall1 [223,[306][307][308]. Aside from homeostatic microglia, intermediate activationstate microglia, DAM, and MGnD microglial phenotypes described by Keren-Shaul, Krasemann, and colleagues, additional transcriptional microglial phenotypes have been recently identified [267,269]. For instance, singlecell sequencing from white and grey matter led to the characterization of White-matter microglia (WAM), which are relevant in the AD context because the brains of AD patients present a high white matter loss, which is also related to motor and cognitive dysfunction [309][310][311]. Prior studies have shown that APOE4 can modulate white matter integrity [312]. ...
Article
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ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
... Moving beyond voxelbased methods, WM fiber orientation distributions (FODs) can be generated from constrained spherical deconvolution methods, which then enables quantification of fiber-specific metrics and improved specificity in regions with crossing fiber tracts. Reduced fiber density has been observed in both MCI (Mito et al., 2018) and AD (Luo et al., 2021) using fixel-based analysis. The COMMIT2 framework augments probabilistic FOD-based tractography using anatomically and microstructure-informed filtering; this robust analysis framework has been demonstrated to dramatically improve the specificity of the estimated brain networks without affecting their sensitivity (Schiavi et al., 2020b). ...
Article
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White matter integrity and structural connectivity may be altered in mild cognitive impairment (MCI), and these changes may closely reflect decline in specific cognitive domains. Multi-shell diffusion data in healthy control (HC, n = 31) and mild cognitive impairment (MCI, n = 19) cohorts were downloaded from the ADNI3 database. The data were analyzed using an advanced approach to assess both white matter microstructural integrity and structural connectivity. Compared with HC, lower intracellular compartment (IC) and higher isotropic (ISO) values were found in MCI. Additionally, significant correlations were found between IC and Montreal Cognitive Assessment (MoCA) scores in the MCI cohort. Network analysis detected structural connectivity differences between the two groups, with lower connectivity in MCI. Additionally, significant differences between HC and MCI were observed for global network efficiency. Our results demonstrate the potential of advanced diffusion MRI biomarkers for understanding brain changes in MCI.
... FBA promotes statistical testing beyond the confinement of a white matter 'skeleton' of classical tract-based statistics, which can be limited by reduced detection accuracy compared to whole-brain analysis 53,54 . Furthermore, FBA is helpful to guard against potential misleading findings in brain areas with complex crossing fibre architecture, that are known to result in erroneously unchanged or increased values of voxel-average DTI metrics such as FA as demonstrated recently in a comparative investigation of patients with Alzheimer's disease 55,56 . ...
Article
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Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population. However, characterizing the disease pathophysiology and its association with potential clinical sequelae in early stages is less well explored. We applied fixel-based analysis (FBA), a novel framework of investigating microstructural white matter integrity by diffusion-weighted imaging, to data of 921 participants of the Hamburg City Health Study, comprising middle-aged individuals with increased cerebrovascular risk in early stages of CSVD. In individuals in the highest quartile of white matter hyperintensity loads (n = 232, median age 63 years; IQR 15.3 years), FBA detected significantly reduced axonal density and increased atrophy of transcallosal fiber tracts, the bilateral superior longitudinal fasciculus, and corticospinal tracts compared to participants in the lowest quartile of white matter hyperintensities (n = 228, mean age 55 years; IQR 10 years). Analysis of all participants (N = 921) demonstrated a significant association between reduced fiber density and worse executive functions operationalized by the Trail Making Test. Findings were confirmed by complementary analysis of diffusion tensor metrics.
... Classical diffusion tensor imaging techniques cannot model crossing fibres that are present in up to 90% of white matter voxels [57][58][59] . FBA is an emerging framework that uses a higher-order diffusion model that estimates the orientations of each fibre population and also quantifies degenerative changes in specific fibre populations within voxels. ...
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Depression is a common non-motor feature of Parkinson’s disease (PD) which confers significant morbidity and is challenging to treat. The thalamus is a key component in the basal ganglia-thalamocortical network critical to the pathogenesis of PD and depression but the precise thalamic subnuclei involved in PD depression have not been identified. We performed structural and diffusion-weighted imaging (DWI) on 76 participants with PD to evaluate the relationship between PD depression and grey and white matter thalamic subnuclear changes. We used a thalamic segmentation method to divide the thalamus into its 50 constituent subnuclei (25 each hemisphere). Fixel-based analysis was used to calculate mean fibre cross-section (FC) for white matter tracts connected to each subnucleus. We assessed volume and FC at baseline and 14–20 months follow-up. A generalised linear mixed model was used to evaluate the relationship between depression, subnuclei volume and mean FC for each thalamic subnucleus. We found that depression scores in PD were associated with lower right pulvinar anterior (PuA) subnucleus volume. Antidepressant use was associated with higher right PuA volume suggesting a possible protective effect of treatment. After follow-up, depression scores were associated with reduced white matter tract macrostructure across almost all tracts connected to thalamic subnuclei. In conclusion, our work implicates the right PuA as a relevant neural structure in PD depression and future work should evaluate its potential as a therapeutic target for PD depression.
... Дегенерация белого вещества описывается как одно из самых ранних изменений мозга при БА, предшествующих формированию амилоидных бляшек и нейрофибриллярных клубков [17]. В частности, предполагается ранняя уязвимость медиальных отделов височных долей и предклинья, трактов белого вещества в своде, поясной извилине и МТ [18]. ...
Article
. Despite a high prevalence of mild cognitive impairment (MCI), there are no accepted algorithms of diff erentiating the syndrome and the prognosis evaluation of later cognitive decline at this time. Objective . To identify biomarkers of poor prognosis in the various MCI types by optimizing neuropsychological examination in combination with MRI morphometry of brain structures. Patients and methods. We examined 45 patients (9 men, 36 women, mean age 72 ± 6.7 years) with MCI according to the modifi ed Petersen’s criteria and the DSM-5 criteria. All patients underwent the MMSE scale, the Detailed Neuropsychological Testing (DNT), which included a Ten Words Test (TWT), a “Double Test” (DT), a visual acuity test, a high-fi eld magnetic resonance imaging (MRI) of the brain with morphometry of cerebral structures (FreeSurfer, FSL). Results . According to the MMSE score, MCI were found in 26 (58%) patients. During the DNT, depending on the state of memory, 14 participants of the study identifi ed a non-amnestic type of MCI (na-MCI), 15 — an amnestic variant with impaired reproduction (ar-MCI), and 16 people — an amnestic type with a primary memory defect (apm-MCI). Volume changes of the anterior corpus callosum segment (CCA) were signifi cantly associated with the Immediate Recall after 4th reading and the Delayed Recall in the general MCI group (rho = 0.58; 0.58; p < 0.05) and the apmMCI group (rho = 0.6; 0.56; p < 0.05). Kruskal–Wallis Test showed that there were signifi cant group diff erences in the volumes of the CCA, right caudate nucleus, left cerebellar hemisphere cortex, posterior corpus callosum segment and left thalamus. At the same time, the fi rst three structures were combined into a set of informative features for differentiating the type of MCI based on the results of Forward stepwise Discriminant Analysis with a 77.3% accurate classifi cation rate (Wilks’s Lambda: 0.35962; approx. F (6.78) = 8.678, p < 0.001). ROC-analysis established the threshold values of the CCA volumes of ≤ 0.05% and the right caudate nucleus volumes of ≤ 0.23% (81.25% sensitivity in both cases; 62.1% and 60.7% specifi city; AUC 0.787 and 0.767; 95% CI 0.639–0.865 and 0.615–0.881; OR 7.1 and 6.7 (95% CI 1.6–30.6 and 1.6–29), associated with a memory defect in persons with MCI, while the ORs are 7.1 and 6.7 (95% CI 1.6–30.6 and 1.6–29), respectively. When both cerebral structures were included in the logit model, 88.6% classifi cation accuracy, 92.6% sensitivity, and 82.4% specifi city of the method were achieved. Conclusion . It has been demonstrated that classifying patients into the various types of MCI based on the data of memory function refl ected by the DNT and supplemented with MRI morphometry of the brain areas may be used as a sensitive and specifi c instrument for determining the category of patients with a high risk of Alzheimer’s disease. A neuropsychological profi le with a defect in primary memory, atrophic changes in anterior segment of the corpus callosum and the right caudate nucleus have been proposed as biomarkers of poor prognosis. Further longitudinal studies are necessary to clarify the proposed biomarkers of poor prognosis information and to detail the mechanisms of the neurodegenerative process.
... It should be noted that CST consists of several crossing fibers that are linked to SLF (Matejko & Ansari, 2015). While crossing fibers can result in unreliable measurement (Mito et al., 2018), it is also possible that the CST and financial awareness associations may be partially driven by SLF connections (Matejko & Ansari, 2015). However, higher resolution studies will be needed to study the influence of each of these crossing fibers. ...
Article
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Financial decision-making (FDM) and awareness of the integrity of one's FDM abilities (or financial awareness) are both critical for preventing financial mistakes. We examined the white matter correlates of these constructs and hypothesized that the tracts connecting the temporal–frontal regions would be most strongly correlated with both FDM and financial awareness. Overall, 49 healthy older adults were included in the FDM analysis and 44 in the financial awareness analyses. The Objective Financial Competency Assessment Inventory was used to measure FDM. Financial awareness was measured by integrating metacognitive ratings into this inventory and was calculated as the degree of overconfidence or underconfidence. Diffusion tensor imaging data were processed with Tracts Constrained by Underlying Anatomy distributed as part of the FreeSurfer analytic suite, which produced average measures of fractional anisotropy and mean diffusivity in 18 white matter tracts along with the overall tract average. As expected, FDM showed the strongest negative associations with average mean diffusivity measure of the superior longitudinal fasciculus -temporal (SLFT; r = −.360, p = .011) and -parietal (r = −.351, p = .014) tracts. After adjusting for FDM, only the association between financial awareness and average mean diffusivity measure of the right SLFT (r = .310, p = .046) was significant. Overlapping white matter tracts were involved in both FDM and financial awareness. More importantly, these preliminary findings reinforce emerging literature on a unique role of right hemisphere temporal connections in supporting financial awareness.
... Classical diffusion tensor imaging techniques cannot model crossing fibres that are present in up to 90% of white matter voxels [57][58][59] . FBA is an emerging framework that uses a higher-order diffusion model that estimates the orientations of each fibre population and also quantifies degenerative changes in specific fibre populations within voxels. ...
Article
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Depression is a common non-motor feature of Parkinson’s disease (PD) which confers significant morbidity and is challenging to treat. The thalamus is a key component in the basal ganglia-thalamocortical network critical to the pathogenesis of PD and depression but the precise thalamic subnuclei involved in PD depression have not been identified. We performed structural and diffusion-weighted imaging (DWI) on 76 participants with PD to evaluate the relationship between PD depression and grey and white matter thalamic subnuclear changes. We used a thalamic segmentation method to divide the thalamus into its 50 constituent subnuclei (25 each hemisphere). Fixel-based analysis was used to calculate mean fibre cross-section (FC) for white matter tracts connected to each subnucleus. We assessed volume and FC at baseline and 14–20 months follow-up. A generalised linear mixed model was used to evaluate the relationship between depression, subnuclei volume and mean FC for each thalamic subnucleus. We found that depression scores in PD were associated with lower right pulvinar anterior (PuA) subnucleus volume. Antidepressant use was associated with higher right PuA volume suggesting a possible protective effect of treatment. After follow-up, depression scores were associated with reduced white matter tract macrostructure across almost all tracts connected to thalamic subnuclei. In conclusion, our work implicates the right PuA as a relevant neural structure in PD depression and future work should evaluate its potential as a therapeutic target for PD depression.
... dMRI tractography has become an indispensable tool for studies on various brain disorders including, but not limited to, multiple sclerosis (MS) ( Fleischer et al., 2019;Sbardella et al., 2013 ), amnestic mild cognitive impairment (aMCI) ( Bai et al., 2009;Zhao et al., 2017a ), Alzheimer's disease ( Jack and Holtzman, 2013;Lo et al., 2010;Mito et al., 2018;Toga and Thompson, 2013 ), stroke ( Mukherjee, 2005 ), schizophrenia ( Collin et al., 2016;Goldsmith et al., 2018;Voineskos, 2014 ), depression ( De Witte andMueller, 2017;Korgaonkar et al., 2014 ), obsessive-compulsive disorder (OCD) ( Cao et al., 2021;Chiu et al., 2011;Gan et al., 2017;Gruner et al., 2012;Koch et al., 2014;Widge et al., 2021 ), attention-deficit hyperactivity disorder (ADHD) ( Cao et al., 2014;2013;Damatac et al., 2020;Hong et al., 2014 ) and autism ( Ikuta et al., 2014;Langen et al., 2012;Thomas et al., 2011;Zhang et al., 2018a ). In this section, we are condensing the explanation using two exemplar disorders, multiple sclerosis and schizophrenia , as the methods utilized in the study of such are representative of the work done across a breadth of disorders. ...
Article
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Diffusion magnetic resonance imaging (dMRI) tractography is an advanced imaging technique that enables in vivo reconstruction of the brain’s white matter connections at macro scale. It provides an important tool for quantitative mapping of the brain’s structural connectivity using measures of connectivity or tissue microstructure. Over the last two decades, the study of brain connectivity using dMRI tractography has played a prominent role in the neuroimaging research landscape. In this paper, we provide a high-level overview of how tractography is used to enable quantitative analysis of the brain’s structural connectivity in health and disease. We focus on two types of quantitative analyses of tractography, including: 1) tract-specific analysis that refers to research that is typically hypothesis-driven and studies particular anatomical fiber tracts, and 2) connectome-based analysis that refers to research that is more data-driven and generally studies the structural connectivity of the entire brain. We first provide a review of methodology involved in three main processing steps that are common across most approaches for quantitative analysis of tractography, including methods for tractography correction, segmentation and quantification. For each step, we aim to describe methodological choices, their popularity, and potential pros and cons. We then review studies that have used quantitative tractography approaches to study the brain’s white matter, focusing on applications in neurodevelopment, aging, neurological disorders, mental disorders, and neurosurgery. We conclude that, while there have been considerable advancements in methodological technologies and breadth of applications, there nevertheless remains no consensus about the “best” methodology in quantitative analysis of tractography, and researchers should remain cautious when interpreting results in research and clinical applications.
... 1,2 WM microstructural deterioration is also observed in specific brain regions in mild cognitive impairment (MCI). 3,4 AD is characterized by a chronic brain glucose deficit, which is already present in older people years before the onset of cognitive decline associated with AD. 5,6 WM energy supply is crucial for adequate axonal function in part because oligodendrocytes need a considerable amount of energy for dynamic remodeling of myelin throughout life. 7 Hence, the gradual brain glucose deficit that begins during aging may lead to declining myelin energy metabolism, myelin loss, and impaired network connectivity, thereby contributing to cognitive dysfunction. ...
Article
The capacity of ketones to improve cognition in mild cognitive impairment (MCI) may depend on ApoE4 status. In the BENEFIC RCT (NCT02551419), improvement in three cognitive domains was directly related to ketones from medium chain triglyceride (kMCT) improving global brain energy status. Post‐kMCT, ketone uptake increased 2.9‐fold in total white matter (WM) and was significantly positively correlated to improved processing speed composite score in 8/9 WM fascicles, especially the fornix (r = 0.47‐0.61; p = 0.014‐0.072; n=16‐17/group). Here we report from the same trial the relationship to both ApoE4(‐) and to WM structural properties post‐intervention. In MCI, cognitive outcomes were assessed before and after a 6‐month intervention involving an active arm (15 g kMCT twice/day; n=39) and placebo arm (non‐ketogenic vegetable oil; n=43), both emulsified into a lactose‐free skim milk drink. Brain imaging (18F‐fluorodeoxyglucose [FDG] and 11C‐acetoacetate PET, diffusion MRI at 3 Tesla) was done on a subset of the main cohort. Participant demographics and imaging methods were previously reported (Fortier et al. Alz Dementia 2019). In ApoE4(‐) participants, two measures of executive function (verbal fluency [p≤0.016] and Stroop total errors [0.008]) improved more post‐kMCT (n=28) compared to placebo (n=32). Faster completion of the Trail‐making test (motor speed and visual scanning conditions that measure attention and processing speed), was also directly correlated to higher ketone uptake in most of these nine fascicles. Six months on kMCT did not significantly affect WM fascicle structural properties measured by diffusion imaging (apparent fiber density, free water). Diffusion‐tensor imaging metrics and FDG uptake were also unaffected in total WM and in most individual fascicles. In MCI, the beneficial effect of kMCT on executive function was greater in ApoE4(‐). Better processing speed and attention was directly linked to improved WM energetics, specifically higher ketone uptake in fascicles affected in AD, but did not alter WM structural properties measurable by diffusion imaging. Ketones improved outcomes in all five main cognitive domains in MCI so a ketone‐based prevention‐type trial to delay the onset of AD is warranted. Acknowledgements: Supported by the Alzheimer Association, Nestlé Health Science, MITACS, FRQS and USherbrooke.
... Fixel-based analysis (FBA) applies the CSD model and can more accurately reconstruct a continuous FOD in both single-and multiple-fiber voxelscharacterizing properties of each "fixel," or specific fiber population in a voxel [21][22][23][24][25]. Fixels can be statistically analyzed for relatively specific indices of underlying fiber physiology: fiber density (FD), a microstructural measure of the within-voxel intra-axonal restricted compartment of a fiber population; fiber cross-section (FC), a macrostructural measure of the area perpendicular to the fiber orientation; and fiber density and cross-section (FDC), a combination of FD and FC [25]. Less FD can indicate axonal loss, while less FC can indicate macroscopic fiber atrophy [26][27][28]. FBA resolves crossing fibers more accurately, as well as characterizes the microstructural and morphological, macrostructural properties of specific fiber populations. ...
Preprint
Background: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18-34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax=1.092, standardized effect[SE]=0.044, pFWE=0.016), and improvement in combined symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax=3.775, SE=0.051, pFWE=0.019). Conclusions: Aberrant white matter development involves both lCST micro- and macrostructural alterations and its path may be moderated by preceding symptom trajectory.
... White matter hyperintensities are most often distributed in the frontal and parietal lobes (Gootjes et al., 2004), with some studies indicating that AD patients may exhibit relatively more WMH in posterior cerebral regions specifically (Brickman, 2013;Yoshita et al., 2006). Additionally, studies utilizing DTI on AD patients have reported widespread degeneration in cerebral WM microstructure (Gold et al., 2012;Mito et al., 2018;Sexton et al., 2011); Specific tracts in the fornix, cingulum and corpus callosum have been implicated to be vulnerable already in preclinical AD (Mak et al., 2017). Interestingly, elevated WMH burden in the general population have also been shown to contribute to brain atrophy in brain regions that often show neuronal loss in AD (Habes et al., 2016). ...
Thesis
Full-text available
Aging is associated with an increased risk for developing vascular pathology in cerebral white matter (WM). These brain changes can have a variety of cognitive repercussions, ranging from insignificant to mild cognitive impairment to dementia. Concomitant WM pathology is also frequently found in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Previous research generally supports the notion that WM pathology and AD-related pathology would have a cumulative impairing effect on cognition, but relatively few studies have focused on studying these effects. Thus, the aim of this thesis was to investigate the effects of WM pathology on cognitive function in cognitively healthy older adults and patients with MCI or AD. Study I investigated the effects of WM pathology on general cognitive functioning as measured by the CERAD-NB and utilized visual ratings of magnetic resonance imaging (MRI) data. Here, AD patients with severe frontal WM pathology had markedly lower performances than AD patients with milder pathology. Study II utilized the same sample as Study I but expanded the scope of analysis to include four specific cognitive domains. Frontal WM pathology was associated with lower cognitive performance in processing speed and visual memory, and parieto-occipital WM pathology solely with processing speed, in all groups. Furthermore, notably slower processing speed performance was seen in AD patients with moderate or severe left frontal WM pathology than in AD patients with less cerebrovascular pathology in that region. Study III included the same four cognitive domains as Study II but utilized quantitative volumetric measurements of WM pathology. A portion of the sample used in Study II had to be excluded due to inadequate MRI resolution, which resulted in combining the MCI and AD groups into a single patient group. Overall, temporal and parieto-occital WM pathology were associated with lower processing speed, and parieto-occipital WM pathology with lower verbal memory. Furthermore, a group-specific effect was seen in the follow-up analyses: Here WM pathology in the left temporal lobe was associated with lower processing speed only in MCI or AD patients. Study IV utilized the same sample and image analysis methods as Study III but focused solely on verbal fluency. Here, WM pathology in bilateral frontal, bilateral parieto-occipital and right temporal areas was associated with semantic fluency in right-handed participants. However, no cumulative effects on verbal fluency impairment were seen specifically in patients with MCI or AD. The results of this thesis support the notion that WM pathology and AD-related pathologies can have cumulative effects on cognition. More specifically, AD patients who have major levels of WM pathology especially in frontal cerebral areas are likely to exhibit more cognitive impairments when compared to patients with milder levels of WM pathology. Impairments may show up as slowed information processing speed and lowered general cognitive functioning, which can be detected with general-level cognitive measures such as the Total Score of the CERAD-NB. As previous studies have shown that the prevalence of WM pathology can be lowered by minimizing modifiable risk factors and fostering physical and cognitive activity, the pre-emptive targeting of these factors is likely to yield long-term benefits in maintaining cognition in MCI and AD.
... 1,2 WM microstructural deterioration is also observed in specific brain regions in mild cognitive impairment (MCI). 3,4 AD is characterized by a chronic brain glucose deficit, which is already present in older people years before the onset of cognitive decline associated with AD. 5,6 WM energy supply is crucial for adequate axonal function in part because oligodendrocytes need a considerable amount of energy for dynamic remodeling of myelin throughout life. 7 Hence, the gradual brain glucose deficit that begins during aging may lead to declining myelin energy metabolism, myelin loss, and impaired network connectivity, thereby contributing to cognitive dysfunction. ...
Article
Full-text available
Introduction: White matter (WM) energy supply is crucial for axonal function and myelin maintenance. An exogenous source of ketones, the brain's alternative fuel to glucose, bypasses the brain's glucose-specific energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). How an additional supply of ketones affects glucose or ketone uptake in specific WM fascicles in MCI has not previously been reported. Methods: This 6-month interventional study included MCI participants randomized to a placebo (n = 16) or ketogenic medium chain triglyceride (kMCT; n = 17) drink. A neurocognitive battery and brain imaging were performed pre- and post-intervention. WM fascicle uptake of ketone and glucose and structural properties were assessed using positron emission tomography and diffusion imaging, respectively. Results: Ketone uptake was increased in the kMCT group by 2.5- to 3.2-fold in all nine WM fascicles of interest (P < .001), an effect seen both in deep WM and in fascicle cortical endpoints. Improvement in processing speed was positively associated with WM ketone uptake globally and in individual fascicles, most importantly the fornix (r = +0.61; P = .014). Discussion: A 6-month kMCT supplement improved WM energy supply in MCI by increasing ketone uptake in WM fascicles. The significant positive association with processing speed suggests that ketones may have a role in myelin integrity in MCI.
... 26 Mito and colleagues revealed significant white matter loss at both the microstructural and macrostructural levels in patients with Alzheimer's disease, which was evident in specific fiber pathways associated with the default mode network node. 27 Taken together, the findings indicated that FA and MD can be used as early predictors of the development of CTN. Clinically, the changes in FA and MD of the left thalamic radiation and the left corticospinal tract, which are associated with sensory input and motor output, suggested projection fiber damage. ...
Article
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Objective To study the characteristics of point-by-point destruction of white matter tracts in patients using automated fiber tract quantification (AFQ). Methods Thirty-four classic trigeminal neuralgia (CTN) patients and 34 healthy control (HC) subjects underwent 3.0 T diffusion tensor magnetic resonance imaging and T1-weighted imaging. The fractional anisotropy (FA) and mean diffusivity (MD) of 100 nodes of 20 fiber tracts were analyzed by AFQ, and the correlations of the FA and MD with the visual analogue scale (VAS) pain score were assessed. Results The FA values of the left thalamic radiation (middle segment), left corticospinal tract, callosum forceps minor, and right uncinate fasciculus were significantly lower in CTN patients than in the HC group. The MD of the left thalamic tract (middle segment), left corticospinal tract, right superior longitudinal fasciculus, and left superior longitudinal fasciculus (anterior segment) were significantly higher in the CTN group. Additionally, the VAS pain score in CTN patients was positively correlated with FA and negatively correlated with MD. Conclusion Specific fiber tract nodes were damaged in CTN patients, which was related to the VAS pain score. Multi-node quantitative studies of fiber tract damage are valuable for understanding the white matter tract damage pattern in CTN patients.
... Over the past decades, Alzheimer's disease (AD) has been conceptualized as a grey matter pathology characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles [1,2]. Nevertheless, numerous neuropathological and neuroimaging studies indicate that white matter (WM) abnormalities are also commonly present among AD patients [3][4][5][6][7][8]. While these findings have been traditionally interpreted as comorbidities, accumulating evidence from our group [9] and others [10][11][12][13][14] points towards a link between WM pathology and AD-specific neuropathologic changes, suggesting that WM degeneration is a characteristic feature of the AD pathological cascade. ...
Article
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Purpose Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored. Methods Participants with concurrent ¹⁸ F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images ( n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. Results In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals. Conclusion These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.
... Despite the fact that diffusion-tensor metrics have well-characterized the voxel-wise microstructural features of WMH regions (Jones et al., 1999;Maniega et al., 2015), these are not well suited to properly characterize microstructural changes in AD-and aging-related studies (Jones et al., 2013;Fu et al., 2020). Misleading results from the diffusion-tensor model were observed in voxels containing more than one fiber population (e.g., at fiber bundle crossings) when comparing controls and AD patients (Mito et al., 2018). This misleading could affect most brain regions because the proportion of these multi-directional voxels is approximately 70-90% in the WM (Jones et al., 2013;Dell'Acqua and Tournier, 2019). ...
Article
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White matter hyperintensities (WMHs) are associated with cognitive decline. Assessing the effect of WMH on WM microstructural changes and its relationships with structural and functional connectivity to multiple cognitive domains are helpful to better understand the pathophysiological processes of cognitive impairment. 65 participants (49 normal and 16 MCI subjects, age: 67.4 ± 8.3 years, 44 females) were studied at 3T. The WMHs and fifty fiber tracts were automatically segmented from the T1/T2-weighted images and diffusion-weighted images, respectively. Tract-profiles of WMH were compared with those of apparent fiber density (AFD). The relationship between AFD and tract connectivity (TC) was assessed. Functional connectivity (FC) between tract ends obtained from resting-state functional MRI was examined in relation to TC. Tract-specific relationships of WMH, TC and FC with a multi-domain neuropsychological test battery and Montreal Cognitive Assessment (MoCA) were also separately assessed by lasso linear regression. Indirect pathways of TC and FC between WMH and multiple cognitive measures were tested using the mediation analysis. Higher WMH loads in WM tracts were locally matched with the reduced AFD, which was related to decrease in TC. However, no direct relationship was found between TC and FC. Tract-specific changes on WMH, TC and FC for each cognitive performance may explain that macro- and microstructural and functional changes are associated differently with each cognitive domain in a fiber specific manner. In these identified tracts, the differences between normal and MCI for WMH and TC were increased, and the relationships of WMH, TC and FC with cognitive outcomes were more significant, compared to the results from all tracts. Indirect pathways of two-step (TC-FC) between WMH and all cognitive domains were significant ( p < 0.0083 with Bonferroni correction), while the separated indirect pathways through TC and through FC were different depending on cognitive domain. Deterioration in specific cognitive domains may be affected by alterations in a set of different tracts that are differently associated with macrostructural, microstructural, and function changes. Thus, assessments of WMH and its associated changes on specific tracts help for better understanding of the interrelationships of multiple changes in cognitive impairment.
... Via these techniques, alterations in the brain of AD patients and of people at risk of developing AD have been identified. AD patients exhibit WM loss in tracts associated with certain default mode network (DMN) nodes (Mito et al., 2018). They also exhibit increased characteristic path length and decreased intramodular connections in functional and structural brain networks compared to healthy controls (Dai et al., 2018). ...
Preprint
To facilitate pre-symptomatic diagnosis of late-onset Alzheimer’s disease, non-invasive imaging biomarkers could be combined with genetic risk information. In this work, we investigated the structural brain networks of young adults in relation to polygenic risk for Alzheimer’s disease, using magnetic resonance imaging (MRI) and genotype data for 564 19-year-old participants from the Avon Longitudinal Study of Parents and Children. Diffusion MRI was acquired on a 3T scanner, and the data were used to perform whole-brain tractography. The resulting tractograms were used to generate structural brain networks, using the number of streamlines and the diffusion tensor fractional anisotropy as edge weights. This was done for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. Graph theoretical metrics were calculated for these networks, for each participant. The hubs of the networks were also identified, and the connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating the burden of genetic risk carried by an individual, were calculated both at genome-wide level and for nine specific disease pathways. The correlation coefficients were calculated between the PRSs and a) the graph theoretical metrics of the structural networks and b) the rich-club, feeder and local connectivity of the whole-brain networks. In the visual subnetwork, the mean nodal strength exhibited a negative correlation with the genome-wide PRS including the APOE locus, while the mean betweenness centrality showed a positive correlation with the pathway-specific PRS for plasma lipoprotein particle assembly including the APOE locus. The rich-club connectivity was reduced in participants with higher genome-wide PRS including the APOE locus. Our results indicate small changes in the brain connectome of young adults at risk of developing Alzheimer’s disease in later life.
... We also evaluated the association between the precision, accuracy, prediction and error correction of rhythmic timing with the properties of the deep WM (dWM). Fixel-based analysis (FBA) (Dhollander et al., 2021;Raffelt et al., 2017) was used to estimate micro and macroestructural differences within-voxel of the dWM (Genc et al., 2018;Kelly et al., 2020;Mito et al., 2018;Rau et al., 2019). As with our analysis of superficial WM, this method is based on the constrained spherical deconvolution (CSD) of DWI data. ...
Preprint
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We determined the intersubject association between rhythmic entrainment abilities of human subjects during a synchronization continuation tapping task (SCT) and the macro and microstructural properties of their superficial (SWM) and deep (dWM) white matter. Diffusion-weighted images were obtained from 32 subjects who also performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the fiber density of U-fibers running tangentially to the cortex. Notably, the right audiomotor system showed individual differences in the density of U-fibers that were correlated with the degree of predictive entrainment across subjects. These correlations were selective for the synchronization epoch with auditory metronomes and were specific for tempos around 1.5 Hz. In addition, there was a significant association between predictive rhythmic entrainment and the density and bundle diameter of the corpus callosum (CC), forming a chronotopic map where behavioural correlations of short and long intervals were found with the anterior and posterior portions of the CC. Finally, the fiber bundle cross-section of the arcuate fasciculus, the CC, and the Superior Longitudinal Fasciculus showed a significant correlation with the mean asynchronies of the auditory SCT. These findings suggest that the structural properties of the SWM and dWM in the audiomotor system support the predictive abilities of subjects during rhythmic tapping, where the density of cortical U-fibers are linked to the preferred tapping tempo, while the bundle properties of CC define an interval selective topography that has an anterior posterior gradient.
... The following FBA steps were processed within MRtrix (Version 3.0.2) (Tournier et al., 2019). Response functions for white matter, grey matter and cerebrospinal fluid were generated for each participant using a fully automated unsupervised algorithm that has been successfully used with lesion data (Dhollander et al., , 2017(Dhollander et al., , 2016Mito et al., 2018a, Mito et al., 2018b. A group averaged response function for each tissue type was created using TDC; patients were left out due to their pathology. ...
Article
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The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.
... Here, we extend previous observations that reported an association between DTI and NFT pathology in the MTL limbic connections and medial parietal WM [12]. Evidence also suggests the association between tau PET and anterior temporal cortex and associated pathways [70], suggesting greater WM vulnerability in tracts associated with early tau accumulation [29,71]. CGH is an important tract connecting the hippocampus to the posterior cingulate cortex, and it has been reported that CGH diffusivity significantly predicts downstream tau accumulation and associated memory decline in amyloid positive individuals [14]. ...
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Multi-compartment modelling of white matter microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on white matter health through neurite density index and free water measures. We hypothesized that cerebrovascular disease, Alzheimer’s disease, and TDP-43 proteinopathy would be associated with distinct NODDI readouts of white matter damage which would be informative for identifying the substrate for cognitive impairment. We identified two independent cohorts with multi-shell diffusion MRI, amyloid and tau PET, and cognitive assessments: specifically, a population-based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota, population and a clinical research-based cohort of 61 amyloid positive Alzheimer’s dementia participants. We observed an increase in free water and decrease in neurite density using NODDI measures in the genu of the corpus callosum associated with vascular risk factors, which we refer to as the vascular white matter component. Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal white matter where we measured parahippocampal cingulum and inferior temporal white matter bundles. Worsening temporal white matter neurite density was associated with (antemortem confirmed) FDG TDP-43 signature. Post-mortem neuropathologic data on a small subset of this sample lend support to our findings. In the community-dwelling cohort where vascular disease was more prevalent, the NODDI vascular white matter component explained variability in global cognition (partial R² of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory). In the AD dementia cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non-trivial contribution of the temporal white matter component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether cerebrovascular disease versus neurodegenerative disease caused by tau deposition or TDP-43 pathology) for cognitive impairment in older adults. Graphical abstract
... The MTL is mainly engaged in episodic memory [55]. The integrity of the cingulum bundle fibers, which are thought to form connections with and among the anterior mPFC, PCC and MTL [13], is compromised in the early stage of AD [56,57]. Notably, the parahippocampal tracts are the critical structures of the DMN and the memory system. ...
Article
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia, and amnestic mild cognitive impairment (aMCI) has been defined as a transitional stage between normal aging and the development of AD. Accumulating evidence has shown that altered functional connectivity (FC) and structural connectivity (SC) in the default mode network (DMN) is the prominent hallmarks of AD. However, the relationship between the changes in SC and FC of the DMN is not yet clear. In the present study, we derived the FC and SC matrices of the DMN with functional magnetic resonance imaging (fMRI) and diffusion-weighted imaging (DWI) data and further assessed FC and SC abnormalities within a discovery dataset of 120 participants (39 normal controls, 34 patients with aMCI and 47 patients with AD), as well as a replication dataset of 122 participants (43 normal controls, 37 patients with aMCI and 42 patients with AD). Disrupted SC and FC were found among DMN components (e.g., the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and hippocampus) in patients in the aMCI and AD groups in the discovery dataset; most of the disrupted connections were also identified in the replication dataset. More importantly, some SC and FC elements were significantly correlated with the cognitive ability of patients with aMCI and AD. In addition, we found structural-functional decoupling between the PCC and the right hippocampus in patients in the aMCI and AD groups. These findings of the alteration of DMN connectivity in neurodegenerative cohorts deepen our understanding of the pathophysiological mechanisms of AD.
... Fixels can be statistically analyzed for fiber-specific indices of underlying physiology: fiber density (FD), a microstructural measure of the within-voxel intra-axonal restricted compartment of a fiber population; fiber cross-section (FC), a macrostructural measure of the area perpendicular to the fiber orientation; and fiber density and cross-section (FDC), a combination of FD and FC (Raffelt et al., 2017b). Less FD can indicate axonal loss, while less FC can indicate macroscopic fiber atrophy (Gajamange et al., 2018;Mito et al., 2018;Rojas-Vite et al., 2019). FBA resolves crossing fibers more accurately as well as characterizes the microstructural and morphological, macrostructural properties of specific fiber populations. ...
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Background Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). Conclusions Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory.
... At the same time, FBA metrics are fiber-specific (a "fixel" refers to an individual fiber population within a voxel), particularly also in the presence of crossing fibers. This is a marked advantage over popular voxel-averaged approaches such as Diffusion Tensor Imaging (DTI), which lack interpretability in the presence of complex fiber arrangements (Jones et al., 2013;Mito et al., 2018). FBA is implemented in the MRtrix software package (Tournier et al., 2019), and has increasingly been used over recent years (Dhollander et al., 2021a). ...
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Introduction Neonatal arterial ischemic stroke (NAIS) has been shown to affect white matter (WM) microstructure beyond the lesion. Here, we employed fixel-based analysis, a technique which allows to model and interpret WM alterations in complex arrangements such as crossing fibers, to further characterize the long-term effects of NAIS on the entire WM outside the primary infarct area. Materials and Methods 32 children (mean age 7.3 years (SD 0.4), 19 male) with middle cerebral artery NAIS (18 left hemisphere, 14 right hemisphere) and 31 healthy controls (mean age 7.7 years (SD 0.6), 16 male) underwent diffusion MRI scans and clinical examination for manual dexterity. Microstructural and macrostructural properties of the WM were investigated in a fixel-based whole-brain analysis, which allows to detect fiber-specific effects. Additionally, tract-averaged fixel metrics in interhemispheric tracts, and their correlation with manual dexterity, were examined. Results Significantly reduced microstructural properties were identified, located within the parietal and temporal WM of the affected hemisphere, as well as within their interhemispheric connecting tracts. Tract-averaged fixel metrics showed moderate, significant correlation with manual dexterity of the affected hand. No increased fixel metrics or contralesional alterations were observed. Discussion Our results show that NAIS leads to long-term alterations in WM microstructure distant from the lesion site, both within the parietal and temporal lobes as well as in their interhemispheric connections. The functional significance of these findings is demonstrated by the correlations with manual dexterity. The localization of alterations in structures highly connected to the lesioned areas shift our perception of NAIS from a focal towards a developmental network injury.
... First, our results showed that the MD of WM networks as features outperformed FA in all the machine learning classifiers ( Figure 5). Second, research showed the sensitivity of the MD index to MCI (Yu et al., 2017), while FA only begins to have statistical differences in multiple fiber tracts during AD (Mito et al., 2018). Our experiment confirmed that the MD index was more sensitive in the MCI stage from classification performance. ...
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Background Detection of mild cognitive impairment (MCI) is essential to screen high risk of Alzheimer’s disease (AD). However, subtle changes during MCI make it challenging to classify in machine learning. The previous pathological analysis pointed out that the hippocampus is the critical hub for the white matter (WM) network of MCI. Damage to the white matter pathways around the hippocampus is the main cause of memory decline in MCI. Therefore, it is vital to biologically extract features from the WM network driven by hippocampus-related regions to improve classification performance.Methods Our study proposes a method for feature extraction of the whole-brain WM network. First, 42 MCI and 54 normal control (NC) subjects were recruited using diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI), and T1-weighted (T1w) imaging. Second, mean diffusivity (MD) and fractional anisotropy (FA) were calculated from DTI, and the whole-brain WM networks were obtained. Third, regions of interest (ROIs) with significant functional connectivity to the hippocampus were selected for feature extraction, and the hippocampus (HIP)-related WM networks were obtained. Furthermore, the rank sum test with Bonferroni correction was used to retain significantly different connectivity between MCI and NC, and significant HIP-related WM networks were obtained. Finally, the classification performances of these three WM networks were compared to select the optimal feature and classifier.Results(1) For the features, the whole-brain WM network, HIP-related WM network, and significant HIP-related WM network are significantly improved in turn. Also, the accuracy of MD networks as features is better than FA. (2) For the classification algorithm, the support vector machine (SVM) classifier with radial basis function, taking the significant HIP-related WM network in MD as a feature, has the optimal classification performance (accuracy = 89.4%, AUC = 0.954). (3) For the pathologic mechanism, the hippocampus and thalamus are crucial hubs of the WM network for MCI.Conclusion Feature extraction from the WM network driven by hippocampus-related regions provides an effective method for the early diagnosis of AD.
... We assessed the fixel-derived metric FDC using both exploratory whole-brain and a priori analyses. As the name suggests, changes in the combined fibre density and cross-section measure reflect both a macroscopic change to the white matter bundle and a microstructural change due to increased or decreased axon fibre population [15,38]. Further, as a fixel-derived metric, FDC can be assessed for specific fibre bundle orientations and hence, specific white matter tracts of interest. ...
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Background Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43ΔNLS), mimicking the key pathology implicated in ALS. Methods Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor performance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna. Results Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss including gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this ALS-like phenotype, these mice have significantly disrupted glymphatic function. Conclusions Although the relationship between glymphatic clearance and ALS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of ALS.
... One important factor leading to these inconsistent findings might again be the relatively small sample sizes (N = 5-18, per group), which emphasizes the need for long-term randomized controlled trials (RCTs) with larger sample sizes. Another problematic factor might be the use of the diffusion tensor model, which can be unreliable and difficult to interpret (Mito et al., 2018). The main issue is that classical DTI analysis estimates one value per voxel and does, therefore, not distinguish different fiber populations within a specific voxel, although findings suggest that these crossing fibers are present in 60-90% of white matter voxels (Jeurissen et al., 2013). ...
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While aging is characterized by neurodegeneration, musical training is associated with experience-driven brain plasticity and protection against age-related cognitive decline. However, evidence for the positive effects of musical training mostly comes from cross-sectional studies while randomized controlled trials with larger sample sizes are rare. The current study compares the influence of six months of piano training with music listening/musical culture lessons in 121 musically naïve healthy elderly individuals with regard to white matter properties using fixel-based analysis. Analyses revealed a significant fiber density decline in the music listening/musical culture group (but not in the piano group), after six months, in the fornix, which is a white matter tract that naturally declines with age. In addition, these changes in fiber density positively correlated to episodic memory task performances and the amount of weekly piano training. These findings not only provide further evidence for the involvement of the fornix in episodic memory encoding but also more importantly show that learning to play the piano at an advanced age may stabilize white matter microstructure of the fornix.
... This approach allows both the diffusion model and the number of distinct fibre populations within a voxel to be estimated from the observed data, and is the basis for voxel-wise estimation of apparent fibre density (AFD) for these distinct populations 14 . Differences in oriented clusters of AFD (also referred to as fixels; 15 ) have been shown for patients with motor neurone disease 14 and Alzheimer's disease 16 . A related spherical deconvolution-based approach, called hindrance modulated orientational anisotropy (HMOA), uses the amplitude of specific lobes of the ODF as an estimate of white matter integrity for a specific fibre population 17 . ...
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Diffusion-weighted neuroimaging approaches provide rich evidence for estimating the structural integrity of white matter in vivo, but typically do not assess white matter integrity for connections between two specific regions of the brain. Here, we present a method for deriving tract-specific diffusion statistics, based upon predefined regions of interest. Our approach derives a population distribution using probabilistic tractography, based on the Nathan Kline Institute (NKI) Enhanced Rockland sample. We determine the most likely geometry of a path between two regions and express this as a spatial distribution. We then estimate the average orientation of streamlines traversing this path, at discrete distances along its trajectory, and the fraction of diffusion directed along this orientation for each participant. The resulting participant-wise metrics (tract-specific anisotropy; TSA) can then be used for statistical analysis on any comparable population. Based on this method, we report both negative and positive associations between age and TSA for two networks derived from published meta-analytic studies (the “default mode” and “what-where” networks), along with more moderate sex differences and age-by-sex interactions. The proposed method can be applied to any arbitrary set of brain regions, to estimate both the spatial trajectory and DWI-based anisotropy specific to those regions.
... One important factor leading to these inconsistent findings might again be the relatively small sample sizes (N = 5-18, per group), which emphasizes the need for long-term randomized controlled trials (RCTs) with larger sample sizes. Another problematic factor might be the use of the diffusion tensor model, which can be unreliable and difficult to interpret (Mito et al., 2018). The main issue is that classical DTI analysis estimates one value per voxel and does, therefore, not distinguish different fiber populations within a specific voxel, although findings suggest that these crossing fibers are present in 60-90% of white matter voxels (Jeurissen et al., 2013). ...
Article
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While aging is characterized by neurodegeneration, musical training is associated with experience-driven brain plasticity and protection against age-related cognitive decline. However, evidence for the positive effects of musical training mostly comes from cross-sectional studies while randomized controlled trials with larger sample sizes are rare. The current study compares the influence of six months of piano training with music listening/musical culture lessons in 121 musically naïve healthy elderly individuals with regard to white matter properties using fixel-based analysis. Analyses revealed a significant fiber density decline in the music listening/musical culture group (but not in the piano group), after six months, in the fornix, which is a white matter tract that naturally declines with age. In addition, these changes in fiber density positively correlated to episodic memory task performances and the amount of weekly piano training. These findings not only provide further evidence for the involvement of the fornix in episodic memory encoding but also more importantly show that learning to play the piano at an advanced age may stabilize white matter microstructure of the fornix.
... This approach examines diffusion properties of individual fibre populations within a voxel instead of estimating a voxel-average measure. 6,35 Moreover, FBA is sensitive to microstructural changes of WM tracts, including FD, FC or both FDC. 12 Using this technique and a permutation method for correcting for multiple comparisons at a whole-brain level, we were able to avoid the ambiguities of previous investigations. The present study also recruited any Canadian individuals who were posted in Havana, without additional criteria based on the presence or Table 2 Structural white matter edges found to have significantly decreased SIFT2-weighted structural connectivity in the exposed cohort relative to the unexposed cohort absence of symptoms. ...
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Diplomats representing the United States have reported with unusual neurologic symptoms and MRI changes after being posted in Havana, Cuba between late 2016 to 2018. Here we examined white matter microstructure and network connectivity of individuals stationed in Havana, using diffusion-weighted MRI, fixel-based analysis, and structural connectomics as implemented in MRtrix3. MRI data acquisition and clinical assessments were done in a total of 24 diplomats and their family members and 40 healthy controls. The diplomat data was grouped into an exposed cohort (n = 16) and an unexposed cohort (n = 10), and among these, 2 individuals were assessed before and after potential exposure. Fixel-based analysis revealed a reduction in fiber density in two specific regions: the fornix and the splenium, in exposed individuals, relative to unexposed individuals and healthy controls. Post-hoc analyses showed the effect remained present (p < 0.05) in both regions when comparing exposed and unexposed diplomats; and reduced fibre density was correlated with longer time period stationed in Cuba after age-correction. Reduction of fibre density was also found to be linked with clinical symptoms of persistent migraine, tinnitus, sound sensitivity and fatigue. Network statistical comparisons revealed decreased structural connectivity in two distinct networks, comprising subcortical and cortical systems in exposed individuals, relative to unexposed and normative data. While the cause for the differences between the groups remains unknown, our results reveal region-specific white matter injury that is significantly correlated with clinical symptoms.
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Objective To identify white matter fibre tracts that exhibit structural abnormality in patients with bottom-of-sulcus dysplasia (BOSD), and investigate their association with seizure activity. Methods Whole-brain fixel-based analysis of diffusion MRI data was performed to identify white matter fibre tracts with significant reductions in fibre density and cross-section in BOSD patients ( n = 20) when compared to healthy control participants ( n = 40). Results from whole-brain analysis were used as priors to investigate the association of fibre tract abnormality with seizure frequency and epilepsy duration. Results Despite the focal nature of the dysplasia, BOSD patients showed widespread abnormality in white matter fibre tracts, including the bilateral corticospinal, corticothalamic, and cerebellothalamic tracts, superior longitudinal fasciculi, corpus callosum (body) and the forceps major. This pattern of bilateral connectivity reduction was not related to the laterality of the lesion. Exploratory post-hoc analyses showed that high seizure frequency was associated with greater reduction in fibre density at the forceps major, bilateral corticospinal and cerebellothalamic tracts. Conclusions We demonstrate evidence of a bilaterally-distributed, specific white matter network that is vulnerable to disruption in BOSD. The degree of tract abnormality is partly related to seizure activity, but additional contributors such as the genetic background and effects of treatment or environment have not been excluded.
Article
White matter (WM) degeneration is suggested to predict the early signs of Alzheimer’s disease (AD). The exact structural regions of brain circuitry involved are not known. This study aims to examine the associations between WM tract integrity, represented by the diffusion tensor imaging (DTI) measures, and AD diagnosis, and to denote the key substrates in predicting AD. It included DTI measures of mean diffusivity (MD), fractional anisotropy, radial diffusivity and axial diffusivity of 18 main WM tracts in 84 non‐Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative dataset. The multivariable general linear model was used to examine the association of AD diagnosis with each DTI measure adjusting for age, gender, and education. The corpus callosum, fornix, cingulum hippocampus, uncinate fasciculus, sagittal striatum, left posterior thalamic radiation and fornix‐stria terminalis showed significant increases in MD, radial and axial diffusivity, whereas the splenium of corpus callosum and the fornix showed significant decreases in fractional anisotropy among AD patients. Variable cluster analysis identified that hippocampus volume, Mini‐Mental State Examination (MMSE), cingulate gyrus/hippocampus, inferior fronto‐occipital fasciculus and uncinate fasciculus are highly correlated in one cluster with MD measures. In conclusion, there were significant differences in DTI measures between the brain WM of AD patients and controls. Age is the risk factor associated with AD, not gender or education. Right cingulum gyrus and right uncinate fasciculus, are particularly affected, correlating well with a cognitive test MMSE and MD measures for dementia in AD patients, and could be a region of focus for AD staging.
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Objective Visual hallucinations are common in Parkinson’s disease (PD) and associated with worse outcomes. Large-scale network imbalance is seen in PD-associated hallucinations, but mechanisms remain unclear. As the thalamus is critical in controlling cortical networks, structural thalamic changes could underlie network dysfunction in PD hallucinations. Methods We used whole-brain fixel-based analysis and cortical thickness measures to examine longitudinal white and grey matter changes in 76 patients with PD (15 hallucinators, 61 non-hallucinators) and 26 controls at baseline, and after 18 months. We compared white matter and cortical thickness, adjusting for age, gender, time-between-scans and intracranial volume. To assess thalamic changes, we extracted volumes for 50 thalamic subnuclei (25 each hemisphere) and mean fibre cross-section (FC) for white matter tracts originating in each subnucleus and examined longitudinal change in PD-hallucinators versus non-hallucinators. Results PD hallucinators showed white matter changes within the corpus callosum at baseline and extensive posterior tract involvement over time. Less extensive cortical thickness changes were only seen after follow-up. White matter connections from the right medial mediodorsal magnocellular thalamic nucleus showed reduced FC in PD hallucinators at baseline followed by volume reductions longitudinally. After follow-up, almost all thalamic subnuclei showed tract losses in PD hallucinators compared with non-hallucinators. Interpretation PD hallucinators show white matter loss particularly in posterior connections and in thalamic nuclei, over time with relatively preserved cortical thickness. The right medial mediodorsal thalamic nucleus shows both connectivity and volume loss in PD hallucinations. Our findings provide mechanistic insights into the drivers of network imbalance in PD hallucinations and potential therapeutic targets.
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Background: Diffusion MRI (dMRI) is known to be sensitive to hypoxic-ischemic encephalopathy (HIE). However, existing dMRI studies used simple diffusion tensor metrics and focused only on a few selected cerebral regions, which cannot provide a comprehensive picture of microstructural injury. Purpose: To systematically characterize the microstructural alterations in mild, moderate, and severe HIE neonates compared to healthy neonates with advanced dMRI using region of interest (ROI), tract, and fixel-based analyses. Study type: Prospective. Population: A total of 42 neonates (24 males and 18 females). Field strength/sequence: 3-T, diffusion-weighted echo-planar imaging. Assessment: Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) were calculated in 40 ROIs and 6 tracts. Fixel-based analysis was performed to assess group differences in individual fiber components within a voxel (fixel). Statistical tests: One-way analysis of covariance (ANCOVA) to compare dMRI metrics among severe/moderate/mild HIE and control groups and general linear model for fixel-wise group differences (age, sex, and body weight as covariates). Adjusted P value < 0.05 was considered statistically significant. Results: For severe HIE, ROI-based analysis revealed widespread regions, including the deep nuclei and white matter with reduced FA, while in moderate injury, only FC was decreased around the posterior watershed zones. Tract-based analysis demonstrated significantly reduced FA, FD, and FC in the right inferior fronto-occipital fasciculus (IFOF), right inferior longitudinal fasciculus (ILF), and splenium of corpus callosum (SCC) in moderate HIE, and in right IFOF and left anterior thalamic radiation (ATR) in mild HIE. Correspondingly, we found altered fixels in the right middle-posterior IFOF and ILF, and in the central-to-right part of SCC in moderate HIE. Data conclusion: For severe HIE, extensive microstructural injury was identified. For moderate-mild HIE, association fiber injury in posterior watershed area with a rightward lateralization was found. Evidence level: 1 TECHNICAL EFFICACY: Stage 3.
Article
A major pathological hallmark of neurodegenerative diseases, including Alzheimer’s, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration.
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Sports-related concussion, a form of mild traumatic brain injury, is characterised by transient disturbances of brain function. There is increasing evidence that functional brain changes may be driven by subtle abnormalities in white matter microstructure, and diffusion MRI has been instrumental in demonstrating these white matter abnormalities in vivo. However, the reported location and direction of the observed white matter changes in mild traumatic brain injury are variable, likely attributable to the inherent limitations of the white matter models used. This cross-sectional study applies an advanced and robust technique known as fixel-based analysis to investigate fibre tract-specific abnormalities in professional Australian Football League players with a recent mild traumatic brain injury. We used the fixel-based analysis framework to identify common abnormalities found in specific fibre tracts in participants with an acute injury (≤ 12 days after injury; n = 14). We then assessed whether similar changes exist in subacute injury (> 12 days and < 3 months after injury; n = 15). The control group was 29 neurologically healthy control participants. We assessed microstructural differences in fibre density and fibre bundle morphology and performed whole-brain fixel-based analysis to compare groups. Subsequent tract-of-interest analyses were performed within five selected white matter tracts to investigate the relationship between the observed tract-specific abnormalities and days since injury and the relationship between these tract-specific changes with cognitive abnormalities. Our whole-brain analyses revealed significant increases in fibre density and bundle cross-section in the acute mild traumatic brain injury group when compared to controls. The acute mild traumatic brain injury group showed even more extensive differences when compared to the subacute injury group than to controls. The fibre structures affected in acute concussion included the corpus callosum, left prefrontal and left parahippocampal white matter. The fibre density and cross-sectional increases were independent of time since injury in the acute injury group, and were not associated with cognitive deficits. Overall, this study demonstrates that acute mild traumatic brain injury is characterised by specific white matter abnormalities, which are compatible with tract-specific cytotoxic oedema. These potential oedematous changes were absent in our subacute mild traumatic brain injury participants, suggesting that they may normalise within 12 days after injury, although subtle abnormalities may persist in the subacute stage. Future longitudinal studies are needed to elucidate individualised recovery after brain injury.
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Background: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.
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It is estimated that in the human brain, short association fibres (SAF) represent more than half of the total white matter volume and their involvement has been implicated in a range of neurological and psychiatric conditions. This population of fibres, however, remains relatively understudied in the neuroimaging literature. Some of the challenges pertinent to the mapping of SAF include their variable anatomical course and proximity to the cortical mantle, leading to partial volume effects and potentially affecting streamline trajectory estimation. This work considers the impact of seeding and filtering strategies and choice of scanner, acquisition, data resampling to propose a whole-brain, surface-based short (≤30-40 mm) SAF tractography approach. The framework is shown to produce longer streamlines with a predilection for connecting gyri as well as high cortical coverage. We further demonstrate that certain areas of subcortical white matter become disproportionally underrepresented in diffusion-weighted MRI data with lower angular and spatial resolution and weaker diffusion weighting; however, collecting data with stronger gradients than are usually available clinically has minimal impact, making our framework translatable to data collected on commonly available hardware. Finally, the tractograms are examined using voxel- and surface-based measures of consistency, demonstrating moderate reliability, low repeatability and high between-subject variability, urging caution when streamline count-based analyses of SAF are performed.
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Cognitive impairment in Parkinson disease (PD) leads to substantial disability. Unlike external manifestations such as tremor, the decay of cognitive function is often an underlying process, and its neuroanatomic substrates are not yet fully elucidated. Knowledge regarding cognitive-related alterations in white matter (WM) pathways helps us understand the mechanisms of cognitive decline in patients with PD. Previous voxel-based analyses with Diffusion tensor imaging (DTI) metrics, such as fractional anisotropy (FA) and mean diffusivity (MD) have uncovered white matter differences in groupwise, but the conclusions were inconsistent. That was partially due to white matter fibers that are known to affect cognition, such as the corpus callosum (CC) and superior longitudinal fasciculus that cross in voxel, and are hard to interpreted by the abovementioned metrics. Furthermore, cognitive decay is a continuous process, it is difficult to reflect the continuous changes of white matter fibers between groups comparison. In the present work, we chose the constrained spherical deconvolution (CSD) and the fixel model, which avoided the effect of crossing fibers. To compare the white matter fiber in different cognitive stages of patients with PD, the results found that the CC, the cingulum bundle (CB), and the corticospinal tract (CST) showed the same trend in the decline of cognitive function, and this change may lead to the impairment of cognitive function. Our findings can help physicians determine the cognitive stage of PD from the perspective of white matter fiber and provide a reference for clinical trials and predictions.
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Recent efforts using diffusion tensor imaging (DTI) have documented white matter (WM) alterations in Alzheimer’s disease (AD). The full potential of whole-brain DTI, however, has not been fully exploited as studies have focused on individual microstructural indices independently. In patients with AD (n = 79), mild (MCI, n = 55) and subjective (SCI, n = 30) cognitive impairment, we applied linked independent component analysis (LICA) to model inter-subject variability across five complementary DTI measures (fractional anisotropy (FA), axial/radial/mean diffusivity, diffusion tensor mode), two crossing fiber measures estimated using a multi-compartment crossing-fiber model reflecting the volume fraction of the dominant (f1) and non-dominant (f2) diffusion orientation, and finally, connectivity density obtained from full-brain probabilistic tractography. The LICA component explaining the largest data variance was highly sensitive to disease severity (AD < MCI < SCI) and revealed widespread coordinated decreases in FA and f1 with increases in all diffusivity measures in AD. Additionally, it reflected regional coordinated decreases and increases in f2, mode and connectivity density, implicating bidirectional alterations of crossing fibers in the fornix, uncinate fasciculi, corpus callosum and major sensorimotor pathways. LICA yielded improved diagnostic classification performance compared to univariate region-of-interest features. Our results document coordinated WM microstructural and connectivity alterations in line with disease severity across the AD continuum.
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Voxel-based analysis of diffusion MRI data is increasingly popular. However, most white matter voxels contain contributions from multiple fibre populations (often referred to as crossing fibres), and therefore voxel-averaged quantitative measures (e.g. fractional anisotropy) are not fibre-specific and have poor interpretability. Using higher-order diffusion models, parameters related to fibre density can be extracted for individual fibre populations within each voxel (‘fixels’), and recent advances in statistics enable the multi-subject analysis of such data. However, investigating within-voxel microscopic fibre density alone does not account for macroscopic differences in the white matter morphology (e.g. the calibre of a fibre bundle). In this work, we introduce a novel method to investigate the latter, which we call fixel-based morphometry (FBM). To obtain a more complete measure related to the total number of white matter axons, information from both within-voxel microscopic fibre density and macroscopic morphology must be combined. We therefore present the FBM method as an integral piece within a comprehensive fixel-based analysis framework to investigate measures of fibre density, fibre-bundle morphology (cross-section), and a combined measure of fibre density and cross-section. We performed simulations to demonstrate the proposed measures using various transformations of a numerical fibre bundle phantom. Finally, we provide an example of such an analysis by comparing a clinical patient group to a healthy control group, which demonstrates that all three measures provide distinct and complementary information. By capturing information from both sources, the combined fibre density and cross-section measure is likely to be more sensitive to certain pathologies and more directly interpretable.
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The cingulum bundle (CB) is a critical white matter fiber tract in the brain, which forms connections between the frontal lobe, parietal lobe and temporal lobe. In non-human primates, the CB is actually divided into distinct subcomponents on the basis of corticocortical connections. However, at present, no study has verified similar distinct subdivisions in the human brain. In this study, we reconstructed these distinct subdivisions in the human brain, and determined their exact cortical connections using high definition fiber tracking (HDFT) technique on 10 healthy adults and a 488-subject template from the Human Connectome Project (HCP-488). Fiber dissections were performed to verify tractography results. Five CB segments were identified. CB-I ran from the subrostral areas to the precuneus and splenium, encircling the corpus callosum (CC). CB-II arched around the splenium and extended anteriorly above the CC to the medial aspect of the superior frontal gyrus (SFG). CB-III connected the superior parietal lobule (SPL) and precuneus with the medial aspect of the SFG. CB-IV was a relatively minor subcomponent from the SPL and precuneus to the frontal region. CB-V, the para-hippocampal cingulum, stemmed from the medial temporal lobe and fanned out to the occipital lobes. Our findings not only provide a more accurate and detailed description on the associated architecture of the subcomponents within the CB, but also offer new insights into the functional role of the CB in the human brain.
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To overcome the fact that the fibre orientation distribution (FOD) from constrained spherical deconvolution (CSD) assumes a single-fibre white matter (WM) response function—and is thus inappropriate and distorted in voxels containing grey matter (GM) or cerebrospinal fluid (CSF)—multi-shell multi-tissue CSD (MSMT-CSD) was proposed. MSMT-CSD can resolve WM, GM and CSF signal contributions, but requires multi-shell data. Very recently, we proposed a novel method that can achieve the same results using just single-shell data. We refer to this method as "single-shell 3-tissue CSD" (SS3T-CSD). Both MSMT-CSD and SS3T-CSD require WM, GM and CSF response functions. These can be obtained from manually selected exemplary voxels of the tissue classes, or via the procedure described initially in the MSMT-CSD paper, which relies on a highly accurately co-registered T1 image. We propose an unsupervised procedure that does not depend on a T1 image, nor registration, and works for both single-shell and multi-shell data.
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Background: White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated. Method: Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract ROIs and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN). Results: WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas. Conclusions: High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function.
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We combined the neuroanatomists' approach of defining a fascicle as all fibers passing through its compact stem with diffusion-weighted tractography to investigate the cortical terminations of two association tracts, the inferior fronto-occipital fasciculus (IFOF) and the uncinate fasciculus (UF), which have recently been implicated in the ventral language circuitry. The aim was to provide a detailed and quantitative description of their terminations in 60 healthy subjects and to do so to apply an anatomical stem-based virtual dissection, mimicking classical post-mortem dissection, to extract with minimal a priori the IFOF and UF from tractography datasets. In both tracts, we consistently observed more extensive termination territories than their conventional definitions, within the middle and superior frontal, superior parietal and angular gyri for the IFOF and the middle frontal gyrus and superior, middle and inferior temporal gyri beyond the temporal pole for the UF. We revealed new insights regarding the internal organization of these tracts by investigating for the first time the frequency, distribution and hemispheric asymmetry of their terminations. Interestingly, we observed a dissociation between the lateral right-lateralized and medial left-lateralized fronto-occipital branches of the IFOF. In the UF, we observed a rightward lateralization of the orbito-frontal and temporal branches. We revealed a more detailed map of the terminations of these fiber pathways that will enable greater specificity for correlating with diseased populations and other behavioral measures. The limitations of the diffusion tensor model in this study are also discussed. We conclude that anatomical stem-based virtual dissection with diffusion tractography is a fruitful method for studying the structural anatomy of the human white matter pathways.
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Constrained spherical deconvolution (CSD) is a robust approach to resolve the fibre orientation distribution (FOD) from diffusion MRI data. However, the FOD from CSD only aims to represent "pure" white matter (WM) and is inappropriate/distorted in regions of (partial voluming with) grey matter (GM) or cerebrospinal fluid (CSF). Multi-shell multi-tissue CSD was proposed to solve this issue by estimating WM/GM/CSF components, but requires multi-shell data to do so. In this work, we provide the first proof that similar results can also be obtained from only simple single-shell (+b=0) data, and propose a novel specialised optimiser that achieves this goal.
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Background and purpose: An increase in brain water diffusivity as measured using magnetic resonance imaging (MRI) has been recently reported in normal-appearing white matter (NAWM) in patients affected by cognitive impairment. However, it remains to be clarified if this reflects an overt neuronal tissue disruption that leads to degenerative or microvascular lesions. This question was addressed by comparing the regional MRI apparent diffusion coefficients (ADCs) of NAWM in patients affected by Alzheimer's disease (AD) or vascular dementia (VaD). The relationships of ADCs with the white-matter hyperintensity (WMH) burden, carotid atherosclerosis, and cognitive performance were also investigated. Methods: Forty-nine AD and 31 VaD patients underwent brain MRI to assess the WMH volume and regional NAWM ADCs, neuropsychological evaluations, and carotid ultrasound to assess the plaque severity and intima-media thickness (IMT). Results: Regional ADCs in NAWM did not differ between VaD and AD patients, while the WMH volume was greater in VaD than in AD patients. The ADC in the anterior corpus callosum was related to the WMH volume, while a greater carotid IMT was positively correlated with the temporal ADC and WMH volume. The memory performance was worse in patients with higher temporal ADCs. Constructional praxis scores were related to ADCs in the frontal, and occipital lobes, in the anterior and posterior corpus callosum as well as to the WMH volume. Abstract reasoning was related to frontal, parietal, and temporal ADCs. Conclusions: Our data show that higher regional ADCs in NAWM are associated with microcirculatory impairment, as depicted by the WMH volume. Moreover, regional ADCs in NAWM are differently associated with the neuropsychological performances in memory, constructional praxia, and abstract reasoning domains.
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Alzheimer’s disease (AD) is the most common form of dementia in elderly people. It is an irreversible and progressive brain disease. In this paper, we utilized diffusion-weighted imaging (DWI) to detect abnormal topological organization of white matter (WM) structural networks. We compared the differences between WM connectivity characteristics at global, regional, and local levels in 26 patients with probable AD and 16 normal control (NC) elderly subjects, using connectivity networks constructed with the diffusion tensor imaging (DTI) model and the high angular resolution diffusion imaging (HARDI) model, respectively. At the global level, we found that the WM structural networks of both AD and NC groups had a small-world topology; however, the AD group showed a significant decrease in both global and local efficiency, but an increase in clustering coefficient and the average shortest path length. We further found that the AD patients had significantly decreased nodal efficiency at the regional level, as well as weaker connections in multiple local cortical and subcortical regions, such as precuneus, temporal lobe, hippocampus, and thalamus. The HARDI model was found to be more advantageous than the DTI model, as it was more sensitive to the deficiencies in AD at all of the three levels.
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Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure-analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both.
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In this paper we describe a method for retrospective estimation and correction of eddy current (EC)-induced distortions and subject movement in diffusion imaging. In addition a susceptibility-induced field can be supplied and will be incorporated into the calculations in a way that accurately reflects that the two fields (susceptibility- and EC-induced) behave differently in the presence of subject movement. The method is based on registering the individual volumes to a model free prediction of what each volume should look like, thereby enabling its use on high b-value data where the contrast is vastly different in different volumes. In addition we show that the linear EC-model commonly used is insufficient for the data used in the present paper (high spatial and angular resolution data acquired with Stejskal–Tanner gradients on a 3 T Siemens Verio, a 3 T Siemens Connectome Skyra or a 7 T Siemens Magnetome scanner) and that a higher order model performs significantly better. The method is already in extensive practical use and is used by four major projects (the WU-UMinn HCP, the MGH HCP, the UK Biobank and the Whitehall studies) to correct for distortions and subject movement.
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In brain regions containing crossing fibre bundles, voxel-average diffusion MRI measures such as Fractional Anisotropy (FA) are difficult to interpret, and lack within-voxel single fibre population specificity. Recent work has focused on the development of more interpretable quantitative measures that can be associated with a specific fibre population within a voxel containing crossing fibres (herein we use fixel to refer to a specific fibre population within a single voxel). Unfortunately, traditional 3D methods for smoothing and cluster-based statistical inference cannot be used for voxel-based analysis of these measures, since the local neighbourhood for smoothing and cluster formation can be ambiguous when adjacent voxels may have different numbers of fixels, or ill-defined when they belong to different tracts. Here we introduce a novel statistical method to perform whole-brain fixel-based analysis called connectivity-based fixel enhancement (CFE). CFE uses probabilistic tractography to identify structurally connected fixels that are likely to share underlying anatomy and pathology. Probabilistic connectivity information is then used for tract-specific smoothing (prior to the statistical analysis) and enhancement of the statistical map (using a threshold-free cluster enhancement-like approach). To investigate the characteristics of the CFE method, we assessed sensitivity and specificity using a large number of combinations of CFE enhancement parameters and smoothing extents, using simulated pathology generated with a range of test-statistic signal-to-noise ratios in five different white matter regions (chosen to cover a broad range of fibre bundle features). The results suggest that CFE input parameters are relatively insensitive to the characteristics of the simulated pathology. We therefore recommend a single set of CFE parameters that should give near optimal results in future studies where the group effect is unknown. We then demonstrate the proposed method by comparing apparent fibre density between motor neurone disease (MND) patients with control subjects. The MND results illustrate the benefit of fixel-specific statistical inference in white matter regions that contain crossing fibres. Copyright © 2015. Published by Elsevier Inc.