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Neuroimaging biomarkers have shown high potential to map the disease processes in the application to neurodegenerative diseases (NDD), e.g., diffusion tensor imaging (DTI). For DTI, the implementation of a standardized scanning and analysis cascade in clinical trials has potential to be further optimized. Over the last few years, various approaches to improve DTI applications to NDD have been developed. The core issue of this review was to address considerations and limitations of DTI in NDD: we discuss suggestions for improvements of DTI applications to NDD. Based on this technical approach, a set of recommendations was proposed for a standardized DTI scan protocol and an analysis cascade of DTI data pre-and postprocessing and statistical analysis. In summary, considering advantages and limitations of the DTI in NDD we suggest improvements for a standardized framework for a DTI-based protocol to be applied to future imaging studies in NDD, towards the goal to proceed to establish DTI as a biomarker in clinical trials in neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Phelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients. Results: CSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer's disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer's disease. Conclusions: In summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof. [ABSTRACT FROM AUTHOR]

Background: For recurrent high-grade glioma, especially glioblastoma, no standard of care treatment exists. Due to the prolongation of progression-free survival and a cortiocosteroid-sparing effect, bevacizumab is often used in this condition. Despite initial clinical responses, there is growing evidence that bevacizumab may potentiate microstructural alterations which may cause cognitive decline, mostly affecting learning and memory. Methods: To investigate bevacizumab-associated microstructural damage of defined regions of interest (ROIs) in the white matter, diffusion tensor imaging (DTI) was performed in 10 patients with a case history or third-party report for neurological dysfunction concerning cognitive performance. Serial DTI data before and under bevacizumab were collected and longitudinal changes of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were assessed in mesiotemporal (hippocampal), frontal, and occipital regions. Results: The longitudinal DTI data under bevacizumab compared to DTI prior to bevacizumab demonstrated a significant decrease in FA and increase in AD and RD both in mesiotemporal (hippocampal) regions and in frontal regions, whereas occipital regions showed no significant alterations in DTI metrics. Conclusion: The regionally impaired microstructure in mesiotemporal (hippocampal) regions and in frontal regions is in line with the fact that neurocognitive impairment in learning and memory is mostly related to hippocampal integrity and attentional control in frontal regions. Further studies could investigate the potential of DTI to assess bevacizumab-associated microstructural damages in vulnerable brain regions. [ABSTRACT FROM AUTHOR]

Background and objective: The neuropathology of amyotrophic lateral sclerosis (ALS) follows a regional distribution pattern in the brain with four stages. Using diffusion tensor imaging (DTI), this pattern can be translated into a tract-based staging scheme to assess cerebral progression in vivo. This study investigates the association between the sequential alteration pattern and disease severity in patients with ALS. Methods: DTI data of 325 patients with ALS and 130 healthy controls were analyzed in a tract of interest (TOI)-based approach. Patients were categorized according to their ALS-FRS-R scores into groups with declining functionality. The fractional anisotropy (FA) values in the tracts associated with neuropathological stages were group-wise compared with healthy controls. Results: The FA in the tracts associated with ALS stages showed a decrease which could be related to the disease severity stratification, i.e., at the group level, the lower the ALS-FRS-R of the categorized patient group, the higher was the effect size of the stage-related tract. In the patient group with the highest ALS-FRS-R, Cohen's d showed a medium effect size in the corticospinal tract and small effect sizes in the other stage-related tracts. Overall, the lower the ALS-FRS-R of the categorized patient group the higher was the effect size of the comparison with healthy controls. Conclusion: The progression of white matter alterations across tracts according to the model of sequential tract involvement is associated with clinical disease severity in patients with ALS, suggesting the use of staging-based DTI as a technical marker for disease progression. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) allows the in vivo imaging of pathological white matter alterations, either with unbiased voxel-wise or hypothesis-guided tract-based analysis. Alterations of diffusion metrics are indicative of the cerebral status of patients with amyotrophic lateral sclerosis (ALS) at the individual level. Using machine learning (ML) models to analyze complex and high-dimensional neuroimaging data sets, new opportunities for DTI-based biomarkers in ALS arise. This review aims to summarize how different ML models based on DTI parameters can be used for supervised diagnostic classifications and to provide individualized patient stratification with unsupervised approaches in ALS. To capture the whole spectrum of neuropathological signatures, DTI might be combined with additional modalities, such as structural T1w 3-D MRI in ML models. To further improve the power of ML in ALS and enable the application of deep learning models, standardized DTI protocols and multi-center collaborations are needed to validate multimodal DTI biomarkers. The application of ML models to multiparametric MRI/multimodal DTI-based data sets will enable a detailed assessment of neuropathological signatures in patients with ALS and the development of novel neuroimaging biomarkers that could be used in the clinical workup. [ABSTRACT FROM AUTHOR]

Introduction: Diffusion tensor imaging (DTI) can be used to map disease progression in amyotrophic lateral sclerosis (ALS) and therefore is a promising candidate for a biomarker in ALS. To this end, longitudinal study protocols need to be optimized and validated regarding group sizes and time intervals between visits. The objective of this study was to assess the influences of sample size, the schedule of follow-up measurements, and measurement uncertainties on the statistical power to optimize longitudinal DTI study protocols in ALS. Patients and methods: To estimate the measurement uncertainty of a tract-of-interest-based DTI approach, longitudinal test-retest measurements were applied first to a normal data set. Then, DTI data sets of 80 patients with ALS and 50 healthy participants were analyzed in the simulation of longitudinal trajectories, that is, longitudinal fractional anisotropy (FA) values for follow-up sessions were simulated for synthetic patient and control groups with different rates of FA decrease in the corticospinal tract. Monte Carlo simulations of synthetic longitudinal study groups were used to estimate the statistical power and thus the potentially needed sample sizes for a various number of scans at one visit, different time intervals between baseline and follow-up measurements, and measurement uncertainties. Results: From the simulation for different longitudinal FA decrease rates, it was found that two scans per session increased the statistical power in the investigated settings unless sample sizes were sufficiently large and time intervals were appropriately long. The positive effect of a second scan per session on the statistical power was particularly pronounced for FA values with high measurement uncertainty, for which the third scan per session increased the statistical power even further. Conclusion: With more than one scan per session, the statistical power of longitudinal DTI studies can be increased in patients with ALS. Consequently, sufficient statistical power can be achieved even with limited sample sizes. An improved longitudinal DTI study protocol contributes to the detection of small changes in diffusion metrics and thereby supports DTI as an applicable and reliable non-invasive biomarker in ALS. [ABSTRACT FROM AUTHOR]

Background: The underlying neuropathological process of amyotrophic lateral sclerosis (ALS) can be classified in a four‐stage sequential pTDP‐43 cerebral propagation scheme. Using diffusion tensor imaging (DTI), in vivo imaging of these stages has already been shown to be feasible for the specific corticoefferent tract systems. Because both cognitive and oculomotor dysfunctions are associated with microstructural changes at the brain level in ALS, a cognitive and an oculomotor staging classification were developed, respectively. The association of these different in vivo staging schemes has not been attempted to date. Methods: A total of 245 patients with ALS underwent DTI, video‐oculography, and cognitive testing using Edinburgh Cognitive and Behavioral ALS Screen (ECAS). A set of tract‐related diffusion metrics, cognitive, and oculomotor parameters was selected for further analysis. Hierarchical and k‐means clustering algorithms were used to obtain an optimal cluster solution. Results: According to cluster analysis, differentiation of patients with ALS into four clusters resulted: Cluster A showed the highest fractional anisotropy (FA) values and thereby the best performances in executive oculomotor tasks and cognitive tests, whereas cluster D showed the lowest FA values, the lowest ECAS scores, and the worst executive oculomotor performance across all clusters. Clusters B and C showed intermediate results regarding parameter values. Discussion: In a multimodal dataset of technical assessments of brain structure and function in ALS, an artificial intelligence‐based cluster analysis showed high congruence of DTI, executive oculomotor function, and neuropsychological performance for mapping in vivo correlates of neuropathological spreading. [ABSTRACT FROM AUTHOR]

Background: Flail arm syndrome is a restricted phenotype of motor neuron disease that is characterized by progressive, predominantly proximal weakness and atrophy of the upper limbs. Objective: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from flail arm syndrome patients using a hypothesis-guided tract-of-interest-based approach to identify in vivo microstructural changes according to a neuropathologically defined amyotrophic lateral sclerosis (ALS)-related pathology of the cortico-efferent tracts. Methods: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the neuropathological ALS-propagation pattern for 43 flail arm syndrome patients vs 43 'classical' ALS patients vs 40 matched controls. Results: The analysis of white matter integrity demonstrated regional FA reductions for the flail arm syndrome group predominantly along the CST. In the tract-specific analysis according to the proposed sequential cerebral pathology pattern of ALS, the flail arm syndrome patients showed significant alterations of the specific tract systems that were identical to 'classical' ALS if compared to controls. Conclusions: The DTI study including the tract-of-interest-based analysis showed a microstructural involvement pattern in the brains of flail arm syndrome patients, supporting the hypothesis that flail arm syndrome is a phenotypical variant of ALS. [ABSTRACT FROM AUTHOR]

Background: The regional distribution of the widespread cerebral morphological alterations in progressive supranuclear palsy (PSP) is considered to include segmental parts of the corpus callosum (CC). Objective: The study was designed to investigate the regional white matter (WM) of the CC by T1 weighted magnetic resonance imaging (T1w MRI) data combined with diffusion tensor imaging (DTI) data in PSP patients, differentiated in the variants Richardson syndrome and PSP-parkinsonism, and to compare them with Parkinson's Disease (PD) patients and healthy controls, in order to identify macro- and micro-structural alterations in vivo. Methods: MRI-based WM mapping was used to perform an operator-independent segmentation for the different CC segments in 66 PSP patients vs. 66 PD patients vs. 44 matched healthy controls. The segmentation was followed by both planimetric and texture analysis of the separated CC areas for the comparison of the three groups. Results were complemented by a DTI-based tract-of-interest analysis of the associated callosal tracts. Results: Significant alterations of the parameters entropy and homogeneity compared to controls were observed for PSP as well as for PD for the CC areas I, II, and III. The inhomogeneity in area II in the PSP cohort was the highest and differed significantly from PD. A combined score was defined as a potential marker for the different types of neurodegenerative parkinsonism; receiver operating characteristics (ROC) curves were calculated with areas under the curve values of 0.86 for PSP vs. controls, 0.72 for PD vs. controls, and 0.69 for PSP vs. PD, respectively. Conclusion: The multiparametric MRI texture and DTI analysis demonstrated extensive alterations of the frontal CC in neurodegenerative parkinsonism, whereas regional CC atrophy cannot be regarded as a constant neuroimaging feature of PSP. Specifically, the comparison PSP vs. PD revealed significant alterations in callosal area II. The combination of the texture and the DTI parameters might contribute as a neuroimaging marker for the assessment of the CC in PSP, including the differentiation vs. PD. [ABSTRACT FROM AUTHOR]

The potential of multiparametric quantitative neuroimaging has been extensively discussed as a diagnostic tool in amyotrophic lateral sclerosis (ALS). In the past, the integration of multimodal, quantitative data into a useful diagnostic classifier was a major challenge. With recent advances in the field, machine learning in a data driven approach is a potential solution: neuroimaging biomarkers in ALS are mainly observed in the cerebral microstructure, with diffusion tensor imaging (DTI) and texture analysis as promising approaches. We set out to combine these neuroimaging markers as age-corrected features in a machine learning model with a cohort of 502 subjects, divided into 404 patients with ALS and 98 healthy controls. We calculated a linear support vector classifier (SVC) which is a very robust model and then verified the results with a multilayer perceptron (MLP)/neural network. Both classifiers were able to separate ALS patients from controls with receiver operating characteristic (ROC) curves showing an area under the curve (AUC) of 0.87–0.88 ("good") for the SVC and 0.88–0.91 ("good" to "excellent") for the MLP. Among the coefficients of the SVC, texture data contributed the most to a correct classification. We consider these results as a proof of concept that demonstrated the power of machine learning in the application of multiparametric quantitative neuroimaging data to ALS. [ABSTRACT FROM AUTHOR]

Background: Over the life span, the diffusion metrics in brain MRI show different, partly nonlinear changes. These age-dependent changes also seem to exhibit regional differences with respect to the brain anatomy. The age correction of a study cohort's diffusion metrics might thus require consideration of age-related factors. Methods: Diffusion tensor imaging data sets were acquired from 219 healthy participants at ages between 19 and 81 years. Fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivity (AD and RD, respectively) maps were analyzed by a tract of interest-based fiber tracking approach. To describe diffusion metrics as a function of the participant age, linear splines were used to perform curve fitting in 21 specific tract systems covering different functional areas and diffusion directions. Results: In the majority of tracts, an interpolation with a change of alteration rate during adult life described the diffusion properties more accurately than a linear model. Consequently, the diffusion properties remained relatively stable until a decrease (of FA) or increase (of MD, AD, and RD) started at a region-specific time point, whereas a uniform change of diffusion properties was observed only in a few tracts. Single tracts, e.g., located in the cerebellum, remained nearly unaltered throughout the ages between 19 and 81 years. Conclusions: Age corrections of diffusion properties should not be applied to all white matter regions and all age spans in the same way. Therefore, we propose three different approaches for age correction based on fiber tracking techniques, i.e., no correction for areas that do not experience age-related changes and two variants of an age correction depending on the age range of the cohort and the tracts considered. [ABSTRACT FROM AUTHOR]

Background: Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods: The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results: Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion: This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype. [ABSTRACT FROM AUTHOR]

Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported. It is not known whether there is any association between these findings. Here, we studied the integrity of the CC in ALS on the morphological, the functional, the electrophysiological, and the clinical level. Twenty-seven right-handed ALS patients and 21 healthy right-handed controls were included. Mirror activity (MA) was quantified using surface EMG. Diffusion tensor imaging tractography was used to segment the CC and quantify fractional anisotropy (FA). We studied the diffusivity of the intra-axonal markers N-acetylaspartate+N-acetyl aspartyl glutamate D(tNAA) within the CC. IHI was studied as a marker of CC function using a double-pulse TMS protocol. ALS patients showed significantly decreased FA in the motor segment of the CC (p < 0.01), and IHI was significantly reduced compared to controls (p = 0.01). However, no differences were observed regarding D(tNAA) and MA. The morphological as well as the functional integrity of the CC are altered in ALS. IHI was reduced in ALS, associated with decreased FA in the motor CC. Patients did not exhibit increased MA. Also, no differences within the CC were observed using diffusion-weighted spectroscopy. IHI might serve as a marker of transcallosal pathway disruption in ALS, even before clinical deficits become apparent. [ABSTRACT FROM AUTHOR]

The understanding of human and non-human microstructural brain alterations in the course of neurodegenerative diseases has substantially improved by the non-invasive magnetic resonance imaging (MRI) technique of diffusion tensor imaging (DTI). Animal models (including disease or knockout models) allow for a variety of experimental manipulations, which are not applicable to humans. Thus, the DTI approach provides a promising tool for cross-species cross-sectional and longitudinal investigations of the neurobiological targets and mechanisms of neurodegeneration. This overview with a systematic review focuses on the principles of DTI analysis as used in studies at the group level in living preclinical models of neurodegeneration. The translational aspect from in-vivo animal models toward (clinical) applications in humans is covered as well as the DTI-based research of the non-human brains' microstructure, the methodological aspects in data processing and analysis, and data interpretation at different abstraction levels. The aim of integrating DTI in multiparametric or multimodal imaging protocols will allow the interrogation of DTI data in terms of directional flow of information and may identify the microstructural underpinnings of neurodegeneration-related patterns. [ABSTRACT FROM AUTHOR]

Introduction: In the last decade, multiparametric magnetic resonance imaging (MRI) has achieved tremendous advances in applications to amyotrophic lateral sclerosis (ALS) to increase the understanding of the associated pathophysiology. The aim of this review is to summarize recent progress in the development of MRI-based techniques aiming to support the clinical diagnosis in ALS. Areas covered: The review of structural and functional MRI applications to ALS and its variants (restricted phenotypes) is focused on the potential of MRI techniques which contribute to the diagnostic work-up of patients with the clinical presentation of a motor neuron disease. The potential of specific MRI methods for patient diagnosis and monitoring is discussed, and the future design of clinical MRI applications to ALS is conceptualized. Expert opinion: Current multiparametric MRI allows for the use as a clinical biological marker and a technical instrument in the clinical diagnosis of patients with ALS and also of patients with ALS variants. Composite neuroimaging indices of specific anatomical areas derived from different MRI techniques might guide in the diagnostic applications to ALS. Such a development of ALS-specific MRI-based composite scores with sufficient discriminative power versus ALS mimics at an individual level requires standardized advanced protocols and comprehensive analysis approaches. [ABSTRACT FROM AUTHOR]

Neuropathological studies revealed the propagation of amyotrophic lateral sclerosis (ALS) in a sequence of four separate disease-related regional patterns. Diffusion tensor imaging (DTI)-based analysis was established for the individual mapping of sequential disease spreading in ALS as the in vivo transfer to neuroimaging. The aim of this review is to summarize cross-sectional and longitudinal results of these technical approaches in ALS as an in vivo tool to image ALS propagation stages. This concept was also applied to restricted phenotypes of ALS, e.g., lower motor neuron disease (LMND) or primary lateral sclerosis (PLS). In summary, the regional disease patterns in the course of ALS have been successfully mapped by DTI in vivo both cross-sectionally and longitudinally so that this technique might have the potential as a read-out in clinical trials. [ABSTRACT FROM AUTHOR]

The investigation of the human oculomotor system by eye movement recordings provides an approach to behavior and its alterations in disease. The neurodegenerative process underlying parkinsonian syndromes, including Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multisystem atrophy (MSA) changes structural and functional brain organization and thus affects eye movement control in a characteristic manner. Video-oculography has been established as a non-invasive recording device for eye movements and systematic investigations of eye movement control in a clinical framework have emerged as a functional diagnostic tool in neurodegenerative parkinsonism. Disease-specific brain atrophy in parkinsonian syndromes has been reported for decades, these findings were refined by studies utilizing diffusion tensor imaging (DTI) and task-based/task-free functional MRI-both MRI techniques revealed disease-specific patterns of altered structural and functional brain organization. Here, characteristic disturbances of eye movement control in parkinsonian syndromes and their correlations with the structural and functional brain network alterations are reviewed. On this basis, we discuss the growing field of graph-based network analysis of the structural and functional connectome as a promising candidate for explaining abnormal phenotypes of eye movement control at the network level, both in health and in disease. [ABSTRACT FROM AUTHOR]

Objective: Neuropathological studies in amyotrophic lateral sclerosis (ALS) have shown a dissemination in a regional sequence in four anatomically defined patterns. The aim of this retrospective study was to see whether longitudinal diffusion tensor imaging (DTI) data support the pathological findings.Methods: The application of DTI analysis to fibre structures that are prone to be involved at each neuropathological pattern of ALS was performed in a monocentre sample of 67 patients with ALS and 31 controls that obtained at least one follow-up scan after a median of 6 months.Results: At the group level, longitudinal ALS data showed significant differences for the stage-related tract systems. At the individual level, 27% of the longitudinally scanned patients with ALS showed an increase in ALS stage, while the remaining were stable or were at the highest ALS stage. Longitudinal fractional anisotropy changes in the respective tract systems correlated significantly with the slope of the revised ALS functional rating scale.Interpretation: The DTI-based protocol was able to image the disease patterns of ALS in vivo cross-sectionally and longitudinally, in support of DTI as a technical marker to image ALS stages. [ABSTRACT FROM AUTHOR]

Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick's disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression. Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after ∼12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression. Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle-bvFTD pattern I; corticostriatal pathway-bvFTD pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III) did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV) reached significance. The findings in the corticospinal tract were due to a "dichotomous" behavior of FA changes there. Conclusion: Longitudinal TOI analysis demonstrated a pattern of whitematter pathways alterations consistent with patterns of pTDP-43 pathology. [ABSTRACT FROM AUTHOR]

The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral microstructural alterations in neurodegenerative diseases is under investigation. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping was applied to the assessment of predefined white matter tracts in amyotrophic lateral sclerosis (ALS), as an example for a rapid progressive neurodegenerative disease. Methods: DTI was performed every 3 months in six patients with ALS (mean (M) = 7.7; range 3 to 15 scans) and in six controls (M = 3; range 2–5 scans) with the identical scanning protocol, resulting in a total of 65 longitudinal DTI datasets. Fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD), and the ratio AD/RD were studied to analyze alterations within the corticospinal tract (CST) which is a prominently affected tract structure in ALS and the tract correlating with Braak’s neuropathological stage 1. A correlation analysis was performed between progression rates based on DTI metrics and the revised ALS functional rating scale (ALS-FRS-R). Results: Patients with ALS showed an FA and AD/RD decline along the CST, while DTI metrics of controls did not change in longitudinal DTI scans. The FA and AD/RD decrease progression correlated significantly with ALS-FRS-R decrease progression. Conclusion: On the basis of the longitudinal assessment, DTI-based metrics can be considered as a possible noninvasive follow-up marker for disease progression in neurodegeneration. This finding was demonstrated here for ALS as a fast progressing neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Characteristic alterations of eye movement control are a common feature of neurodegenerative parkinsonism, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Regional microstructural alterations as assessed by diffusion tensor imaging (DTI) have been reported in PD, PSP, and MSA. Therefore, we investigated the specific association between eye movement disturbances and microstructural impairment in these diseases. Video-oculographic recordings of smooth pursuit and visually guided reactive saccades as well as fractional anisotropy (FA) maps computed from whole-brain DTI data were analyzed for 36 PD, 30 PSP, 18 MSA patients, and 23 matched healthy control subjects. In PSP, peak eye velocity was pathologically slowed compared to controls ( p < 0.001) and correlated significantly with microstructural impairment in the midbrain ( p < 0.001, corrected). Smooth pursuit eye movements were substantially disturbed in MSA mainly by characteristic 'catch-up' saccades resulting in significantly reduced pursuit gain ( p < 0.001, corrected), and the shape of saccadized pursuit in MSA was significantly correlated with FA reductions in the middle cerebral peduncle ( p < 0.001, FDR corrected). The prevalence of saccadic intrusions as a measure for inhibitory control was significantly increased in PD compared with controls ( p < 0.001), but was uncorrelated with FA in cortical and subcortical white matter. Eye movement disturbances in PSP and MSA-but not in PD-are associated with diagnosis-specific regional microstructural alterations in the white matter. The non-invasive quantified oculomotor function analysis can give clues to the underlying structural connectivity network pathology and underpins its role as a technical marker in PSP and MSA. [ABSTRACT FROM AUTHOR]

Objective: To investigate radiation therapy-induced microstructural damage of white matter in patients with high-grade glioma by diffusion tensor imaging (DTI). Methods: DTI was performed in 18 patients with high-grade glioma (WHO grades III and IV) and 13 healthy controls. DTI images were cross-sectionally aligned for the calculation of baseline fractional anisotropy (FA). Interhemispheric FA values in patients with highgrade glioma before or without brain radiation therapy were compared with the interhemispheric FA values in patients after radiation therapy and in healthy controls. In a subgroup without any clinical or diagnostic evidence of tumor progression, serial DTI data (5-11 scans) before and after radiation therapy were collected and longitudinal interhemispheric FA changes were assessed and compared to longitudinal data from the control group. In addition, interhemispheric axial, mean, and radial diffusivity was assessed. Results: Global interhemispheric FA reductions could be detected cross-sectionally in patients after radiation therapy; these were significantly different from global interhemispheric FA differences both in patients without radiation and in healthy controls. Longitudinal scans in patients with radiation therapy confirmed these findings and revealed progressive microstructural white matter damage after partial brain radiotherapy. The additional DTI metrics axial diffusion, mean diffusivity, and radial diffusion confirmed interhemispheric differences in patients without or before radiation therapy, which were lower than the differences in patients after radiation therapy, although not reaching significance. Conclusion: Interhemispheric global FA differences could potentially serve as a biological marker for irradiation-induced microstructural white matter damage. [ABSTRACT FROM AUTHOR]

Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain major issues in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of whole brain based diffusion tensor imaging (DTI) to delineate alterations of corticoefferent pathways in vivo. Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Furthermore, tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p < 0.05 (corrected for multiple comparisons). Fast progressing LMND showed substantial CST involvement, while slow progressors showed less CST alterations. In the tract-specific analysis according to the ALS-staging pattern as suggested by Braak, fast progressing LMND showed significant alterations of ALS-related tract systems beyond the CST compared to slow progressors and controls. In clinically pure LMND patients, the involvement of corticoefferent fibers was demonstrated, in particular along the CST, supporting the hypothesis that LMND is a phenotypical variant of ALS. This finding suggests to treat these patients like ALS, including the opportunity to participate in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size.Methods: 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups.Results: Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings.Interpretation: This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS. [ABSTRACT FROM AUTHOR]

In Huntington's disease, the relationship of brain structure, brain function and clinical measures remains incompletely understood. We asked how sensory-motor network brain structure and neural activity relate to each other and to motor performance. Thirty-four early stage HD and 32 age- and sex-matched healthy control participants underwent structural magnetic resonance imaging (MRI), diffusion tensor, and intrinsic functional connectivity MRI. Diffusivity patterns were assessed in the cortico-spinal tract and the thalamus-somatosensory cortex tract. For the motor network connectivity analyses the dominant M1 motor cortex region and for the basal ganglia-thalamic network the thalamus were used as seeds. Region to region structural and functional connectivity was examined between thalamus and somatosensory cortex. Fractional anisotropy (FA) was higher in HD than controls in the basal ganglia, and lower in the external and internal capsule, in the thalamus, and in subcortical white matter. Between-group axial and radial diffusivity differences were more prominent than differences in FA, and correlated with motor performance. Within the motor network, the insula was less connected in HD than in controls, with the degree of connection correlating with motor scores. The basal ganglia-thalamic network's connectivity differed in the insula and basal ganglia. Tract specific white matter diffusivity and functional connectivity were not correlated. In HD sensory-motor white matter organization and functional connectivity in a motor network were independently associated with motor performance. The lack of tract-specific association of structure and function suggests that functional adaptation to structural loss differs between participants. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is one of the core elements within the differential diagnostic work-up of patients with neurodegenerative diseases such as dementia syndromes, Parkinsonian syndromes, and motor neuron diseases. Currently, computerized MRI analyses are not routinely used for individual diagnosis; however, they have improved the anatomical understanding of pathomorphological alterations in various neurodegenerative diseases by quantitative comparisons between patients and controls at the group level. For multiparametric MRI protocols, including T1-weighted MRI, diffusion-weighted imaging, and intrinsic functional connectivity MRI, the potential as a surrogate marker is a subject of investigation. The additional value of MRI with respect to diagnosis at the individual level and for future disease-modifying multicentre trials remains to be defined. Here, we give an overview of recent applications of multiparametric MRI to patients with various neurodegenerative diseases. Starting from applications at the group level, continuous progress of a transfer to individual diagnostic classification is ongoing. [ABSTRACT FROM PUBLISHER]

Diffusion tensor imaging (DTI) for assessing ALS-associated white matter alterations has still not reached the level of a neuroimaging biomarker. Since large-scale multicentre DTI studies in ALS may be hampered by differences in scanning protocols, an approach for pooling of DTI data acquired with different protocols was investigated. Three hundred and nine datasets from 170 ALS patients and 139 controls were collected ex post facto from a monocentric database reflecting different scanning protocols. A 3D correction algorithm was introduced for a combined analysis of DTI metrics despite different acquisition protocols, with the focus on the CST as the tract correlate of ALS neuropathological stage 1. A homogenous set of data was obtained by application of 3D correction matrices. Results showed that a fractional anisotropy (FA) threshold of 0.41 could be defined to discriminate ALS patients from controls (sensitivity/specificity, 74%/72%). For the remaining test sample, sensitivity/specificity values of 68%/74% were obtained. In conclusion, the objective was to merge data recorded with different DTI protocols with 3D correction matrices for analyses at group level. These post processing tools might facilitate analysis of large study samples in a multicentre setting for DTI analysis at group level to aid in establishing DTI as a non-invasive biomarker for ALS. [ABSTRACT FROM AUTHOR]

Background: Frontal lobe involvement is considered a clinical and magnetic resonance imaging (MRI) feature in later stages of progressive supranuclear palsy (PSP). Objective: Diffusion tensor imaging (DTI) was used to investigate the integrity of frontal pathways in PSP and Parkinson's disease (PD) patients. Methods: DTI and 3-D MRI were performed in 15 PSP patients (parkinsonism subtype: n = 8; Richardson subtype: n = 7), 15 PD patients, and 18 matched controls. DTI analysis was performed in order to identify differences along frontal white matter structures including the corpus callosum (CC) and was complemented by atlas-based volumetry and planimetry. Results: Significantly reduced regional fractional anisotropy was observed for PSP patients versus controls and PSP versus PD patients, respectively, in frontal areas including the area II of the CC and bilaterally in the callosal radiation. The DTI findings correlated with frontal lobe volumes. These differences were not observed between PD patients and controls. Conclusion: DTI identified a PSP-associated microstructural alteration pattern in the frontal lobes and in the CC area II including the corresponding bilateral callosal radiation tracts that could not be identified in both control samples, supporting the prominent PSP-associated frontal involvement as a potential neuroimaging marker. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In amyotrophic lateral sclerosis (ALS), cognition is affected. Cortical atrophy in frontal and temporal areas has been associated with the cognitive profile of patients. Additionally, reduced metabolic turnover and regional cerebral blood flow in frontal areas indicative of reduced neural activity have been reported for ALS. We hypothesize that functional connectivity in non-task associated functional default mode network (DMN) is associated with cognitive profile and white matter integrity. This study focused on specific cognitive tasks known to be impaired in ALS such as verbal fluency and attention, and the relationship with functional connectivity in the DMN and white matter integrity. Nine patients and 11 controls were measured with an extensive neuropsychological battery. Resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were acquired. Results showed that ALS patients performed significantly worse in attention and verbal fluency task. Patients showed increased functional connectivity in parahippocampal and parietal areas of the non-task associated DMN compared to controls. The more pronounced the cognitive deficits, the stronger the increase in functional connectivity in those areas. White matter integrity was reduced in frontal areas in the patients. In conclusion, increased connectivity in the DMN in parahippocampal and parietal areas might represent recruitment of accessory brain regions to compensate for dysfunctional frontal networks. [ABSTRACT FROM AUTHOR]

Recent work has suggested that progression of amyotrophic lateral sclerosis (ALS) occurs in four stages. Kassubek et al. use a new DTI-based approach to analyse the fibre tracts prone to be affected at each stage. DTI abnormalities correlate with neuropathology, enabling in vivo imaging of disease stages in ALS.Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for individual clinical work-up purposes, but enlarges the spectrum of potential non-invasive surrogate markers as a neuroimaging-based read-out for amyotrophic lateral sclerosis studies within a clinical context. [ABSTRACT FROM PUBLISHER]

Introduction: Fast in-vivo high resolution diffusion tensor imaging (DTI) of the mouse brain has recently been shown to enable cohort studies by the combination of appropriate pulse sequences and cryogenically cooled resonators (CCR). The objective of this study was to apply this DTI approach at the group level to β-amyloid precursor protein (APP) transgenic mice. Methods: Twelve mice (5 wild type, 7 APP transgenic tg2576) underwent DTI examination at 1562×250 µm3 spatial resolution with a CCR at ultrahigh field (11.7 T). Diffusion images were acquired along 30 gradient directions plus 5 references without diffusion encoding with a total acquisition time of 35 minutes. Fractional anisotropy (FA) maps were statistically compared by whole brain-based spatial statistics (WBSS) at the group level vs. wild type controls. Results: FA-map comparison showed characteristic regional patterns of differences between the groups with localizations associated with Alzheimer’s disease in humans, such as the hippocampus, the entorhinal cortex, and the caudoputamen. Conclusion: In this proof-of-principle study, regions associated with amyloid-β deposition could be identified by WBSS of FA maps in APP transgenic mice vs. wild type mice. Thus, DTI in the mouse brain acquired at 11.7 T by use of a CCR was demonstrated to be feasible for cohort studies. [ABSTRACT FROM AUTHOR]

Introduction: In-vivo high resolution diffusion tensor imaging (DTI) of the mouse brain is often limited by the low signal to noise ratio (SNR) resulting from the required small voxel sizes. Recently, cryogenically cooled resonators (CCR) have demonstrated significant increase of the effective SNR. It is the objective of this study to enable fast DTI of the mouse brain. In this context, CCRs appear attractive for SNR improvement. Methods: Three mice underwent a DTI examination at 1562×250 μm3 spatial resolution with a CCR at ultrahigh field (11.7T). Diffusion images were acquired along 30 gradient directions plus 5 references without diffusion encoding, resulting in a total acquisition time of 35 minutes. For comparison, mice additionally underwent a standardized 110 minutes acquisition protocol published earlier. Fractional anisotropy (FA) and fiber tracking (FT) results including quantitative tractwise fractional anisotropy statistics (TFAS) were qualitatively and quantitatively compared. Results: Qualitative and quantitative assessment of the calculated fractional anisotropy maps and fibre tracking results showed coinciding outcome comparing 35 minute scans to the standardized 110 minute scan. Coefficients of variation for ROI-based FA-comparison as well as for TFAS revealed comparable results for the different scanning protocols. Conclusion: Mouse DTI at 11.7 T was performed with an acquisition time of approximately 30 minutes, which is considered feasible for cohort studies. The rapid acquisition protocol reveals reliable and reproducible FA-values and FT reconstructions, thus allowing an experimental setup for in-vivo large scale whole brain murine DTI cohort studies. [ABSTRACT FROM AUTHOR]

This study was designed to investigate differences of white matter (WM) involvement patterns in various motor neuron disorders (MND) by use of diffusion tensor imaging (DTI).DTI was acquired in ALS ( n == 20), primary lateral sclerosis ( n == 20), pure hereditary spastic paraparesis (HSP) ( n == 20), and complicated HSP ( n == 12). The data analysis was performed by voxelwise comparison of fractional anisotropy (FA) maps at group level together with fibre tracking in regions of interest (ROI) accompanied by tractwise fractional anisotropy statistics. DTI analysis revealed widespread patterns of alterations with a predominant deterioration of the motor system. These alterations encompassed, as the key structures, not only the corticospinal tracts (CST) but also distinct areas of the corpus callosum (CC), in particular its motor segment III. In conclusion, whole brain-based and tract-based DTI analysis was able to define a distinct WM pathoanatomy of different MND. These results may serve as an additional guidance in the identification of MRI-based parameters by showing a consistent CST and CC involvement, with differences in the extent of pathology, across a range of clinically different disorders. For potential future developments in MRI diagnostics in MND, a (perhaps multiparametric) ROI-based approach should include CST and the CC motor segment. [ABSTRACT FROM AUTHOR]

INTRODUCTION In order to obtain detailed information on disease-associated changes in the integrity of cerebral white matter (WM), complementary image analysis (CIA) was applied to patients with amyotrophic lateral sclerosis (ALS) and controls. METHODS Both diffusion tensor imaging and T1-weighted 3-dimensional data were analyzed with respect to WM microstructure and T1 signal intensity alterations, respectively, in a sample of 19 ALS patients. Covariate information was added in the form of clinical parameters. All results were obtained in one common analysis software environment (Tensor Imaging and Fiber Tracking). RESULTS Complementary analysis and display were performed for WM directionality and structure. Significant WM differences between ALS patients and controls were observed both in the motor system, that is, the bilateral corticospinal tracts, and in extramotor brain areas, in part correlating with clinical parameters. The performance of all analyses in one software environment enabled the synopsis of results obtained from various analyses. DISCUSSION/CONCLUSION Within the application of CIA to a neurodegenerative disease for the whole brainbased analysis of WM alterations together with clinical characteristics, it could be demonstrated that ALS was associated with WM changes within and outside the motor system. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Diffusion tensor imaging (DTI) provides comprehensive information about quantitative diffusion and connectivity in the human brain. Transformation into stereotactic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The objective of the present study was to optimize technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. Methods: Different averaging methods for mean diffusion-weighted images containing DTI information were compared, i.e., region of interest-based fractional anisotropy (FA) mapping, fiber tracking (FT) and corresponding tractwise FA statistics (TFAS). The novel technique of intersubject FT that takes into account directional information of single data sets during the FT process was compared to standard FT techniques. Application of the methods was shown in the comparison of normal subjects and subjects with defined white matter pathology (alterations of the corpus callosum). Results: Fiber tracking was applied to averaged data sets and showed similar results compared with FT on single subject data. The application of TFAS to averaged data showed averaged FA values around 0.4 for normal controls. The values were in the range of the standard deviation for averaged FA values for TFAS applied to single subject data. These results were independent of the applied averaging technique. A significant reduction of the averaged FA values was found in comparison to TFAS applied to data from subjects with defined white matter pathology (FA around 0.2). Conclusion: The applicability of FT techniques in the analysis of different subjects at the group level was demonstrated. Group comparisons as well as FT on group averaged data were shown to be feasible. The objective of this work was to identify the most appropriate method for intersubject averaging and group comparison which incorporates intersubject variability of the directional information. [Copyright &y& Elsevier]

Background: In vivo diffusion tensor imaging (DTI) of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis (ALS). Methods: Ten mice with TDP-43G298S overexpression under control of the Thy1.2 promoter and 10 wild type (wt) underwent longitudinal DTI scans at 11.7 T, including one baseline and one follow-up scan with an interval of about 5 months. Whole brain-based spatial statistics (WBSS) of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43G298S mice compared to wt at the cohort level. Results were supplemented by tractwise fractional anisotropy statistics (TFAS) and histological evaluation of motor cortex for signs of neuronal loss. Results: Alterations at the cohort level in TDP-43G298S mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract. Neuronal loss in layer V of motor cortex was detected in TDP-43G298S at the later (but not at the earlier) timepoint compared to wt. Conclusion: DTI mapping of TDP-43G298S mice demonstrated progression in motor areas M1/M2. WBSS and TFAS are useful techniques to localize TDP-43G298S associated alterations over time in this ALS mouse model, as a biological marker. [ABSTRACT FROM AUTHOR]

Background: The nonmotor symptom spectrum of Parkinson's disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia. Methods: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures. Results: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score. Conclusions: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia. [ABSTRACT FROM AUTHOR]