Quantitative iron-neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification.

Background: Neuromelanin- and iron-sensitive MRI studies in Parkinson's disease (PD) are limited by small sample sizes and lack detailed clinical correlation. In a large case-control PD cohort, we evaluated the diagnostic accuracy of quantitative iron-neuromelanin MRI parameters from the substantia nigra (SN), their radiological utility, and clinical association. Methods: PD patients and age-matched controls were prospectively recruited for motor assessment and midbrain neuromelanin- and iron-sensitive [quantitative susceptibility mapping (QSM) and susceptibility map-weighted imaging (SMWI)] MRI. Quantitative neuromelanin-iron parameters from the SN were assessed for their discriminatory performance in PD classification using ROC analysis compared to those of qualitative visual classification by radiological readers of differential experience and used to predict motor severity. Results: In total, 191 subjects (80 PD, mean age 65.0 years; 111 controls, 65.6) were included. SN masks showed (a) higher mean susceptibility (p < 0.0001) and smaller sizes after thresholding for low susceptibility (p < 0.0001) on QSM and (b) lower contrast range (p < 0.0001) and smaller sizes after thresholding for high-signal voxels (p < 0.0001) on neuromelanin-sensitive MRI in patients than in controls. Quantitative iron and neuromelanin parameters showed a moderate correlation with motor dysfunction (87.5%: 0.4< | r | <0.6, p < 0.0001), respectively. A composite quantitative neuromelanin-iron marker differentiated the groups with excellent performance (AUC 0.94), matching the diagnostic accuracy of the best-performing reader (accuracy 97%) using SMWI. Conclusion: Quantitative neuromelanin-iron MRI is associated with PD motor severity and matched best-performing radiological PD classification using SMWI, with the potential to improve diagnostic confidence in the clinics and track disease progression and response to neuroprotective therapies.

Ultra-high-field 7T MRI in Parkinson's disease: ready for clinical use?-a narrative review.

Background and Objective: The maturation of ultra-high-field magnetic resonance imaging (MRI) [≥7 Tesla (7T)] has improved our capability to depict and characterise brain structures efficiently, with better signal-to-noise ratio (SNR) and spatial resolution. We evaluated whether these improvements benefit the clinical detection and management of Parkinson's disease (PD). Methods: We performed a literature search in March 2023 in PubMed (MEDLINE), EMBASE and Google Scholar for articles on "7T MRI" AND "Parkinson*", written in English, published between inception and 1st March, 2023, which we synthesised in narrative form. Key Content and Findings: In deep-brain stimulation (DBS) surgical planning, early studies show that 7T MRI can distinguish anatomical substructures, and that this results in reduced adverse effects. In other areas, while there is strong evidence for improved accuracy and precision of 7T MRI-based measurements for PD, there is limited evidence for meaningful clinical translation. In particular, neuromelanin-iron complex quantification and visualisation in midbrain nuclei is enhanced, enabling depiction of nigrosomes 1-5, improved morphometry and vastly improved radiological assessments; however, studies on the related clinical outcomes, diagnosis, subtyping, differentiation of atypical parkinsonisms, and monitoring of treatment response using 7T MRI are lacking. Moreover, improvements in clinical utility must be great enough to justify the additional costs. Conclusions: Together, current evidence supports feasible future clinical implementation of 7T MRI for PD. Future impacts to clinical decision making for diagnosis, differentiation, and monitoring of progression or treatment response are likely; however, to achieve this, further longitudinal studies using 7T MRI are needed in prodromal, early-stage PD and parkinsonism cohorts focusing on clinical translational potential.

Serial deep gray nuclear DTI changes in Parkinson's disease over twelve years.

Background: Deep gray nuclear pathology relates to motor deterioration in idiopathic Parkinson's disease (PD). Inconsistent deep nuclear diffusion tensor imaging (DTI) findings in cross-sectional or short-term longitudinal studies have been reported. Long-term studies in PD are clinically challenging; decade-long deep nuclear DTI data are nonexistent. We investigated serial DTI changes and clinical utility in a case-control PD cohort of 149 subjects (72 patients/77 controls) over 12 years. Methods: Participating subjects underwent brain MRI at 1.5T; DTI metrics from segmented masks of caudate, putamen, globus pallidus and thalamus were extracted from three timepoints with 6-year gaps. Patients underwent clinical assessment, including Unified Parkinson Disease Rating Scale Part 3 (UPDRS-III) and Hoehn and Yahr (H&Y) staging. A multivariate linear mixed-effects regression model with adjustments for age and gender was used to assess between-group differences in DTI metrics at each timepoint. Partial Pearson correlation analysis was used to correlate clinical motor scores with DTI metrics over time. Results: MD progressively increased over time and was higher in the putamen (p < 0.001) and globus pallidus (p = 0.002). FA increased (p < 0.05) in the thalamus at year six, and decreased in the putamen and globus pallidus at year 12. Putaminal (p = 0.0210), pallidal (p = 0.0066) and caudate MD (p < 0.0001) correlated with disease duration. Caudate MD (p < 0.05) also correlated with UPDRS-III and H&Y scores. Conclusion: Pallido-putaminal MD showed differential neurodegeneration in PD over 12 years on longitudinal DTI; putaminal and thalamic FA changes were complex. Caudate MD could serve as a surrogate marker to track late PD progression.

Microstructure of Brain Nuclei in Early Parkinson's Disease: Longitudinal Diffusion Kurtosis Imaging.

BACKGROUND: Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson's disease. OBJECTIVE: To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson's disease over two years, and whether they correlate with disease progression. METHODS: We conducted a longitudinal case-control study of early Parkinson's disease. 262 people (Parkinson's disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. RESULTS: At baseline, mean kurtosis was higher in Parkinson's disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson's disease group while remaining stable for the control group; evident in significant "group ×time" interaction effects for the putamen, thalamus and globus pallidus (ηp2= 0.08-0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson's disease group. CONCLUSION: Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.

Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson's Disease.

BACKGROUND: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. OBJECTIVE: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). METHODS: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. RESULTS: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. CONCLUSION: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

Recent advances in using diffusion tensor imaging to study white matter alterations in Parkinson's disease: A mini review.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease with cardinal motor symptoms. In addition to motor symptoms, PD is a heterogeneous disease accompanied by many non-motor symptoms that dominate the clinical manifestations in different stages or subtypes of PD, such as cognitive impairments. The heterogeneity of PD suggests widespread brain structural changes, and axonal involvement appears to be critical to the pathophysiology of PD. As α-synuclein pathology has been suggested to cause axonal changes followed by neuronal degeneration, diffusion tensor imaging (DTI) as an in vivo imaging technique emerges to characterize early detectable white matter changes due to PD. Here, we reviewed the past 5-year literature to show how DTI has helped identify axonal abnormalities at different PD stages or in different PD subtypes and atypical parkinsonism. We also showed the recent clinical utilities of DTI tractography in interventional treatments such as deep brain stimulation (DBS). Mounting evidence supported by multisite DTI data suggests that DTI along with the advanced analytic methods, can delineate dynamic pathophysiological processes from the early to late PD stages and differentiate distinct structural networks affected in PD and other parkinsonism syndromes. It indicates that DTI, along with recent advanced analytic methods, can assist future interventional studies in optimizing treatments for PD patients with different clinical conditions and risk profiles.

Seizure Frequency Is Associated with Effective Connectivity of the Hippocampal-Diencephalic-Cingulate in Epilepsy with Unilateral Mesial Temporal Sclerosis.

Background: Temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) is a common intractable epilepsy. To seek neural correlates of seizure recurrence, this study investigated aberrant intrinsic effective connectivity (iEC) in TLE with unilateral MTS and their associations with seizure frequency. Methods: Thirty patients with unilateral MTS (left/right MTS = 14/16) and 37 age-matched healthy controls underwent resting-state functional magnetic resonance imaging (rsfMRI) on a 3-Tesla magnetic resonance imaging (MRI) system. The structural equation modeling was employed to estimate the iEC of the three candidate epilepsy models, including the Papez circuit, hippocampal-diencephalic-cingulate (HDC) model, and simplified HDC model. After comparing the performance of model fitting, the best model was selected to compare iEC among the study groups. The linear regression analysis was performed to associate abnormal iEC with seizure frequency. Results: The simplified HDC model was the best model to estimate iEC across the three study groups (p < 0.05), and it composed of the 26 interconnected pathway between the mesial temporal lobe, thalamus, and cingulate cortices. The linear regression analysis revealed a significant relationship between the shared iEC alterations in both patient groups and seizure frequency (adjusted-R2 = 0.350; p = 0.037), including the three paths of mammillary body (MB) → bilateral anterior thalamic nuclei (left: standardized ß-value = 0.580, p = 0.013; right: standardized ß-value = -0.711, p = 0.006) and right hippocampus → MB (standardized ß-value = 0.541, p = 0.045). Conclusions: Our findings provide new insights into neurophysiological significance relevant to seizure recurrence. Aberrant iEC on the neural paths connected to the MB can be a potential imaging marker, aiding the therapeutic management in TLE with unilateral MTS. Impact statement Within the simplified hippocampal-diencephalic-cingulate model, we identified that altered intrinsic effective connectivity (iEC) on the three paths connecting to the mammillary body was common in temporal lobe epilepsy (TLE) with left and right mesial temporal sclerosis (MTS) and was associated with seizure frequency. Therefore, these common iEC alterations could be a potential imaging marker, aiding the therapeutic management in patients with TLE with unilateral MTS.

Evaluation of trigeminal nerve tractography using two-fold-accelerated simultaneous multi-slice readout-segmented echo planar diffusion tensor imaging.

OBJECTIVES: Simultaneous multi-slice (SMS) imaging with short repetition time (TR) accelerates diffusion tensor imaging (DTI) acquisitions. However, its impact when combined with readout-segmented echo planar imaging (RESOLVE) on the cranial nerves given the challenging skull base/posterior fossa terrain is unexplored. We evaluated the reliability of trigeminal nerve DTI metrics using SMS with RESOLVE-DTI. METHODS: Eight healthy controls and six patients with unilateral trigeminal neuralgia (TN) underwent brain MRI scan. Three different RESOLVE-DTI protocols were performed on a 3-T MRI system: non-SMS (TR = 4330 ms), SMS with identical TR (4330 ms), and SMS with short TR (2400 ms). Pontine signal-to-noise ratio (SNR) and DTI metrics of the trigeminal nerve streamlines tracked by two independent raters using deterministic tractography and standardized tracking protocol were obtained. These were statistically analyzed and compared across the three protocols using intra-rater and inter-rater intraclass correlation coefficients (ICCs), one-way analysis of variance (ANOVA), post hoc analysis, and linear regression. RESULTS: On visual screening, there were no artifacts across the trigeminal nerves. All data also cleared objective image quality assurance analysis. Pontine SNR was similar for the two SMS protocols and higher for the non-SMS RESOLVE-DTI (F(2,36) = 4.40, p = 0.02). Intra-rater and inter-rater ICCs were very good (> 0.85). Trigeminal nerve DTI metrics were consistently measured by the three protocols, revealing significant linear relationships between non-SMS- and SMS-derived DTI metrics. CONCLUSION: SMS RESOLVE-DTI enables fast and reliable evaluation of microstructural integrity of the trigeminal nerve, with potential application in the clinical management of TN. KEY POINTS: • Readout-segmented diffusion-weighted echo planar imaging (RESOLVE-DTI) reduces image distortion artifacts in the posterior fossa but its long acquisition time limits clinical utility. • Simultaneous multi-slice (SMS) imaging combined with RESOLVE-DTI provides reliable trigeminal nerve tractography with potential applications in trigeminal neuralgia. • Two-fold-accelerated RESOLVE-DTI yields comparable trigeminal nerve streamlines and DTI metrics while near-halving acquisition time.

Ultrastructural and diffusion tensor imaging studies reveal axon abnormalities in Pompe disease mice.

Pompe disease (PD) is caused by lysosomal glycogen accumulation in tissues, including muscles and the central nervous system (CNS). The intravenous infusion of recombinant human acid alpha-glucosidase (rhGAA) rescues the muscle pathologies in PD but does not treat the CNS because rhGAA does not cross the blood-brain barrier (BBB). To understand the CNS pathologies in PD, control and PD mice were followed and analyzed at 9 and 18 months with brain structural and ultrastructural studies. T2-weighted brain magnetic resonance imaging studies revealed the progressive dilatation of the lateral ventricles and thinning of the corpus callosum in PD mice. Electron microscopy (EM) studies at the genu of the corpus callosum revealed glycogen accumulation, an increase in nerve fiber size variation, a decrease in the g-ratio (axon diameter/total fiber diameter), and myelin sheath decompaction. The morphology of oligodendrocytes was normal. Diffusion tensor imaging (DTI) studies at the corpus callosum revealed an increase in axial diffusivity (AD) and mean diffusivity (MD) more significantly in 9-month-old PD mice. The current study suggests that axon degeneration and axon loss occur in aged PD mice and are probably caused by glycogen accumulation in neurons. A drug crossing the BBB or a treatment for directly targeting the brain might be necessary in PD.

Premature white matter aging in patients with right mesial temporal lobe epilepsy: A machine learning approach based on diffusion MRI data.

Brain age prediction based on machine learning has been applied to various neurological diseases to discover its clinical values. By this innovative approach, it has been reported that the patients with refractory epilepsy had premature brain aging. Of refractory epilepsy, right and left subtypes of mesial temporal lobe epilepsy (MTLE) are the most common forms and exhibit distinct patterns in white matter alterations. So far, it is unclear whether these two subtypes of MTLE would have difference in white matter aging due to distinct white matter alterations. To address this issue, a machine learning based brain age model using diffusion MRI data was established to investigate biological age of white matter tracts. All diffusion MRI datasets were obtained from the same 3-Tesla MRI scanner. To build the brain age prediction model, diffusion MRI datasets of 300 healthy participants were processed to extract age-relevant diffusion indices from 76 major white matter tracts. The extracted diffusion indices underwent Gaussian process regression to build the prediction model for white matter brain age. The model was validated in an independent testing set (N = 40) to ensure no overfitting of the model. The model was then applied to patients with right and left MTLE and matched controls (right MTLE: N = 17, left MTLE: N = 18, controls: N = 37), and predicted age difference (PAD) was obtained by calculating the difference between each individual's predicted brain age and chronological age. The higher PAD score indicated older brain age. The results showed that right MTLE exhibited older predicted brain age than the other two groups (PAD of right MTLE = 10.9 years [p < 0.05 against left MTLE; p < 0.001 against control]; PAD of left MTLE = 2.2 years [p > 0.1 against control]; PAD of controls = 0.82 years). Patients with right and left MTLE showed strong correlations of the PAD scores with age of onset and duration of illness, but both groups showed opposite directions of correlations. In right MTLE, positive correlation of PAD with seizure frequency was found, and the right uncinate fasciculus was the most attributable tract to the increase in PAD. In conclusion, the present study found that patients with right MTLE exhibited premature white matter brain aging and their PAD scores were correlated with seizure frequency. Therefore, PAD is a potentially useful indicator of white matter impairment and disease severity in patients with right MTLE.

White matter microstructural alterations in amblyopic adults revealed by diffusion spectrum imaging with systematic tract-based automatic analysis.

BACKGROUND/AIM: We investigated the microstructural changes in white matter of adults with amblyopia using diffusion spectrum imaging with systematic tract-based automatic analysis of the whole brain. METHODS: Ten adults with amblyopia (six women and four men, 33.6±10.6 years old on average) and 20 age- and sex-matched normal-sighted controls were enrolled. The mean generalised fractional anisotropy (GFA) was measured in 76 white matter tracts and compared between the experimental and control groups using a threshold-free cluster-weighted method and t-test. A 2-percentile cut-off was used to identify segments with the greatest differences between the two groups. RESULTS: Participants with amblyopia had significantly lower GFA values than the controls in 11 segments located in nine white matter tracts, which included the following: left arcuate fasciculus, left frontal aslant tract, left fornix and left inferior fronto-occipital fasciculus of the association fibres; left thalamic radiations of the auditory nerve and bilateral optic radiations of the projection fibres; and genu and middle temporal gyrus of the callosal fibres. Amblyopic participants had statistically higher GFA values in the bilateral uncinate fasciculus than those of the controls. CONCLUSION: This preliminary study using whole-brain tractographic analysis of white matter reveals association between abnormal early visual processing and alterations in brain architecture, which may be related to various higher-level deficits, such as audiovisual integration and hand-eye coordination in patients with amblyopia.

Altered Cortical Thickness and Tract Integrity of the Mirror Neuron System and Associated Social Communication in Autism Spectrum Disorder.

Previous studies using neural activity recording and neuroimaging techniques have reported functional deficits in the mirror neuron system (MNS) for individuals with autism spectrum disorder (ASD). However, a few studies focusing on gray and white matter structures of the MNS have yielded inconsistent results. The current study recruited adolescents and young adults with ASD (aged 15-26 years) and age-matched typically developing (TD) controls (aged 14-25 years). The cortical thickness (CT) and microstructural integrity of the tracts connecting the regions forming the classical MNS were investigated. High-resolution T1-weighted imaging and diffusion spectrum imaging were performed to quantify the CT and tract integrity, respectively. The structural covariance of the CT of the MNS regions revealed a weaker coordination of the MNS network in ASD. A strong correlation was found between the integrity of the right frontoparietal tracts and the social communication subscores measured by the Chinese version of the Social Communication Questionnaire. The results showed that there were no significant mean differences in the CTs and tract integrity between the ASD and TD groups, but revealed a moderate or even reverse age effect on the frontal MNS structures in ASD. In conclusion, aberrant structural coordination may be an underlying factor affecting the function of the MNS in ASD patients. The association between the right frontoparietal tracts and social communication performance implies a neural correlate of communication processing in the autistic brain. This study provides evidence of abnormal MNS structures and their influence on social communication in individuals with ASD.

Regional cingulum disruption, not gray matter atrophy, detects cognitive changes in amnestic mild cognitive impairment subtypes.

Amnestic mild cognitive impairment (aMCI), which has a high risk of progression to Alzheimer's disease (AD), can be classified into single domain (S-aMCI) and multiple domain (M-aMCI) subtypes. We investigated the integrity of regional gray matter and segments of the cingulum bundle with diffusion spectrum imaging tract-specific analysis, and their relationships to neuropsychological functioning, in 46 individuals with aMCI (S-aMCI n = 24; M-aMCI n = 22) and 36 healthy controls (HC). Results demonstrated that although both aMCI groups were impaired on all memory measures relative to HCs, the M-aMCI group demonstrated worse performance on paired association memory and on selective executive function relative to the S-aMCI group. The two aMCI groups did not show significant atrophy in regional gray matter indices as compared to the HC group, but the M-aMCI group showed significant disruption in white matter of the left anterior and inferior cingulum bundles relative to the S-aMCI and HC groups. Furthermore, disruption in the inferior cingulum bundles was significantly associated with executive function and attention/processing speed in all aMCI participants above and beyond the contribution of bilateral hippocampal volumes. Overall, these results indicate that the degeneration of cingulum fibers did not appear to arise from degeneration of the corresponding cerebral cortex. It also suggests relatively greater sensitivity of a white matter biomarker and comprehensive neuropsychological evaluation over gray matter biomarkers in early detection of AD.

Cingulum correlates of cognitive functions in patients with mild cognitive impairment and early Alzheimer's disease: a diffusion spectrum imaging study.

Diffusion spectrum imaging (DSI) of MRI can detect neural fiber tract changes. We investigated integrity of cingulum bundle (CB) in patients with mild cognitive impairment (MCI) and early Alzheimer's disease (EAD) using DSI tractography and explored its relationship with cognitive functions. We recruited 8 patients with MCI, 9 with EAD and 15 healthy controls (HC). All subjects received a battery of neuropsychological tests to access their executive, memory and language functions. We used a 3.0-tesla MRI scanner to obtain T1- and T2-weighted images for anatomy and used a pulsed gradient twice-refocused spin-echo diffusion echo-planar imaging sequence to acquire DSI. Patients with EAD performed significantly poorer than the HC on most tests in executive and memory functions. Significantly smaller general fractional anisotropy (GFA) values were found in the posterior and inferior segments of left CB and of the anterior segment of right CB of the EAD compared with those of the HC. Spearman's correlation on the patient groups showed that GFA values of the posterior segment of the left CB were significantly negatively associated with the time used to complete Color Trails Test Part II and positively correlated with performance of the logical memory and visual reproduction. GFA values of inferior segment of bilateral CB were positively associated with the performance of visual recognition. DSI tractography demonstrates significant preferential degeneration of the CB on the left side in patients with EAD. The location-specific degeneration is associated with corresponding declines in both executive and memory functions.