Both noise-floor and tissue compartment difference in diffusivity contribute to FA dependence on b-value in diffusion MRI.

Noninvasive diffusion magnetic resonance imaging (dMRI) has been widely employed in both clinical and research settings to investigate brain tissue microstructure. Despite the evidence that dMRI-derived fractional anisotropy (FA) correlates with white matter properties, the metric is not specific. Recent studies have reported that FA is dependent on the b-value, and its origin has primarily been attributed to either the influence of microstructure or the noise-floor effect. A systematic investigation into the inter-relationship of these two effects is however still lacking. This study aims to quantify contributions of the reported differences in intra- and extra-neurite diffusivity to the observed changes in FA, in addition to the noise in measurements. We used in-vivo and post-mortem human brain imaging, as well as numerical simulations and histological validation, for this purpose. Our investigations reveal that the percentage difference of FA between b-values (pdFA) has significant positive associations with neurite density index (NDI), which is derived from in-vivo neurite orientation dispersion and density imaging (NODDI), or Bielschowsky's silver impregnation (BIEL) staining sections of fixed post-mortem human brain samples. Furthermore, such an association is found to be varied with Signal-to-Noise Ratio (SNR) level, indicating a nonlinear interaction effect between tissue microstructure and noise. Finally, a multicompartment model simulation revealed that these findings can be driven by differing diffusivities of intra- and extra-neurite compartments in tissue, with the noise-floor further amplifying the effect. In conclusion, both the differences in intra- and extra-neurite diffusivity and noise-floor effects significantly contribute to the FA difference associated with the b-value.

Free-Water Imaging of the Substantia Nigra in GBA Pathogenic Variant Carriers.

BACKGROUND: Pathogenic variants in the glucocerebrosidase gene (GBA) have been identified as the most common genetic risk factor for Parkinson's disease (PD). However, the features of substantia nigra damage in GBA pathogenic variant carriers remain unclear. OBJECTIVE: We aimed to evaluate the microstructural changes in the substantia nigra in non-manifesting GBA pathogenic variant carriers (GBA-NMC) and PD patients with GBA pathogenic variant (GBA-PD) with free-water imaging. METHODS: First, we compared free water values in the posterior substantia nigra between non-manifesting non-carriers (NMNC, n = 29), GBA-NMC (n = 26), and GBA-PD (n = 16). Then, free water values in the posterior substantia nigra were compared between GBA-PD and early- (n = 19) and late-onset (n = 40) idiopathic PD (iPD) patients. Furthermore, we examined whether the baseline free water values could predict the progressions of clinical symptoms. RESULTS: The free water values in the posterior substantia nigra were significantly higher in the GBA-NMC and GBA-PD groups compared to NMNC, and were significantly increased in the GBA-PD group than both early- and late-onset iPD. Free water values in the posterior substantia nigra could predict the progression of anxiety and cognitive decline in GBA-NMC and GBA-PD groups. CONCLUSIONS: We demonstrate that free water values are elevated in the substantia nigra and predict the development of non-motor symptoms in GBA-NMC and GBA-PD. Our findings demonstrate that a significant nigral impairment already exists in GBA-NMC, and nigral injury may be more severe in GBA-PD than in iPD. These results support that free-water imaging can as a potential early marker of substantia nigra damage. © 2023 International Parkinson and Movement Disorder Society.

Increased Free Water in the Putamen in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies. METHODS: Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed. RESULTS: Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits. CONCLUSIONS: This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.

Evaluation of the diffusion MRI white matter tract integrity model using myelin histology and Monte-Carlo simulations.

Quantitative evaluation of brain myelination has drawn considerable attention. Conventional diffusion-based magnetic resonance imaging models, including diffusion tensor imaging and diffusion kurtosis imaging (DKI),1 have been used to infer the microstructure and its changes in neurological diseases. White matter tract integrity (WMTI) was proposed as a biophysical model to relate the DKI-derived metrics to the underlying microstructure. Although the model has been validated on ex vivo animal brains, it was not well evaluated with ex vivo human brains. In this study, histological samples (namely corpus callosum) from postmortem human brains have been investigated based on WMTI analyses on a clinical 3T scanner and comparisons with gold standard myelin staining in proteolipid protein and Luxol fast blue. In addition, Monte Carlo simulations were conducted to link changes from ex vivo to in vivo conditions based on the microscale parameters of water diffusivity and permeability. The results show that WMTI metrics, including axonal water fraction AWF, radial extra-axonal diffusivity De⊥, and intra-axonal diffusivity Dawere needed to characterize myelin content alterations. Thus, WMTI model metrics are shown to be promising candidates as sensitive biomarkers of demyelination.

Iron accumulation in the ventral tegmental area in Parkinson's disease.

Introduction: The ventral tegmental area (VTA) is less affected compared to substantia nigra pars compacta (SNc) in Parkinson's disease (PD). This study aimed to quantitatively evaluate iron content in the VTA across different stages of PD in order to help explain the selective loss of dopamine neurons in PD. Methods: Quantitative susceptibility mapping (QSM) data were obtained from 101 PD patients, 35 idiopathic rapid eye movement sleep behavior disorder (RBD) patients, and 62 healthy controls (HCs). The mean QSM values in the VTA and SNc were calculated and compared among the groups. Results: Both RBD and PD patients had increased iron values in the bilateral SNc compared with HCs. RBD and PD patients in the Hoehn-Yahr (H & Y) stage 1 did not show elevated iron values in the VTA, while PD patients with more than 1.5 H & Y staging had increased iron values in bilateral VTA compared to HCs. Discussion: This study shows that there is no increased iron accumulation in the VTA during the prodromal and early clinical stages of PD, but iron deposition increases significantly as the disease becomes more severe.

Connectivity of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P carriers.

BACKGROUND: Neuroimaging studies have shown that the functional connectivity (FC) of corticostriatal circuits in nonmanifesting leucine-rich repeat kinase 2 (LRRK2) G2019S mutation carriers mirrors neural changes in idiopathic Parkinson's disease (PD). In contrast, neural network changes in LRRK2 G2385R and R1628P mutations are unclear. We aimed to investigate the FC of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P mutation carriers (NMCs). METHODS: Twenty-three NMCs, 28 PD patients, and 29 nonmanifesting noncarriers (NMNCs) were recruited. LRRK2 mutation analysis was performed on all participants. Clinical evaluation included MDS-UPDRS. RESULTS: When compared to NMNCs, NMCs showed significantly reduced FC between the caudate nucleus and superior frontal gyrus and cerebellum, and between the nucleus accumbens and parahippocampal gyrus, amygdala, and insula. We also found increased striatum-cortical FC in NMCs. CONCLUSIONS: Although the corticostriatal circuits have characteristic changes similar to PD, the relatively intact function of the sensorimotor striatum-cortical loop may result in less possibility of developing parkinsonian motor symptoms for the NMCs. This study helps explain why LRRK2 G2385R and R1628P mutations are risk factors rather than pathogenic mutations for PD and suggests that various LRRK2 mutations have distinct effects on neural networks.

Quantitative Susceptibility Mapping and Free Water Imaging of Substantia Nigra in Parkinson's Disease.

BACKGROUND: The utility of imaging methods to detect iron content in the substantia nigra pars compacta (SNc) and free water imaging in the posterior substantia nigra (pSN) has the potential to be imaging markers for the detection of Parkinson's disease (PD). OBJECTIVE: This study aimed to compare the discriminative power of above methods, and whether the combination can improve the diagnostic potential of PD. METHODS: Quantitative susceptibility mapping (QSM) and diffusion-weighted data were obtained from 41 healthy controls (HC), 37 patients with idiopathic REM sleep behavior disorder (RBD), and 65 patients with PD. Mean QSM values of bilateral SNc and mean isotropic volume fraction (Viso) values of bilateral pSN (mean QSM|Viso values of bilateral SNc|pSN) were separately calculated and compared among the groups. RESULTS: Mean QSM|Viso values of bilateral SNc|pSN were significantly higher for RBD and PD patients compared to HC and were significantly higher in PD patients than in RBD patients. The power of the mean QSM|Viso values of bilateral SNc|pSN and combined mean QSM and Viso values was 0.873, 0.870, and 0.961 in discriminating PD and HC, 0.779, 0.719, and 0.864 in discriminating RBD from HC, 0.634, 0.636, and 0.689 in discriminating PD and RBD patients. CONCLUSION: QSM and free water imaging have similar discriminative power in the detection of prodromal and clinical PD, while combination of these two methods increases discriminative power. Our findings suggest that the combination of QSM and free water imaging has the potential to become an imaging marker for the diagnosis of PD.