Xiaojun Guan

Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping.

The progression of Parkinsons disease (PD) seems to vary according to the disease stage, which greatly influences the management of PD patients. However, the underlying mechanism of progression in PD remains unclear. This study was designed to explore the progressive pattern of iron accumulation at different stages in PD patients. Sixty right‐handed PD patients and 40 normal controls were recruited. According to the disease stage, 45 patients with Hoehn–Yahr stage ≤ 2.5 and 15 patients with Hoehn–Yahr stage ≥ 3 were grouped into early‐stage PD (EPD) and late‐stage PD (LPD) groups, respectively. The iron content in the cardinal subcortical nuclei covering the cerebrum, cerebellum and midbrain was measured using quantitative susceptibility mapping (QSM). The substantia nigra pars compacta (SNc) showed significantly increased QSM values in the EPD patients compared with the controls. In the LPD patients, while the SNc continued to show increased QSM values compared with the controls and EPD patients, the regions showing increased QSM values spread to include the substantia nigra pars reticulata (SNr), red nucleus (RN) and globus pallidus (GP). Our data also indicated that iron deposition was more significant in the GP internal segment (GPi) than in the GP external segment. No other regions showed significant changes in QSM values among the groups. Therefore, we were able to confirm a regionally progressive pattern of iron accumulation in the different stages of PD, indicating that iron deposition in the SNc is affected exclusively in the early stages of the disease, while the SNr, RN and GP, and particularly the GPi segment, become involved in advanced stages of the disease. This is a preliminary study providing objective evidence of the iron‐related progression in PD. Copyright

Influence of regional iron on the motor impairments of Parkinson's disease: A quantitative susceptibility mapping study

Because the roles of striatal‐thalamo‐cortical and cerebello‐thalamo‐cortical circuits in the heterogeneous motor impairments of Parkinsons disease (PD) are becoming recognized, this study was designed to investigate the relationships between regional iron in the cardinal subcortical nuclei in these circuits and the different motor impairments.

Cortical abnormalities in Parkinson’s disease patients and relationship to depression: A surface-based morphometry study

Depression is a common occurrence in patients with Parkinsons disease (PD). Brain deficits may be the underlying cause of depression in PD. In the present study, we investigated whether morphometric alterations contribute to depression in PD. Seventeen depressed PD patients, 17 non-depressed PD patients and 45 normal controls were enrolled in the study. All subjects went through neurological and psychiatric clinical assessments. T1 weighted magnetic resonance imaging and surface-based morphometric analyses were performed to examine morphometric abnormalities in PD patients and their relationship to depression. We found that compared with normal controls, PD patients exhibited significantly decreased cortical thickness in the left precentral gyrus and the right postcentral gyrus extending to the middle frontal gyrus. Compared with non-depressed PD patients, depressed patients showed significantly increased cortical areas in the orbitofrontal regions and insula, which may imply white matter atrophy in these areas. The results of orbitofrontal and insula white matter atrophy are consistent with our previous finding that white matter integrity and functional connectivity are damaged in these regions in depressed PD patients, confirming their contribution to depression in PD.

Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study

Objective It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method There were 135 healthy elderly (including ε2, ε4 allele carriers and ε3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimers disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results We found that APOE ε4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE ε4 carriers had significantly decreased Aβ1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and ε4 allele was related with declining trend of cognition. Conclusion Our findings suggested APOE ε4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and ε4 allele can exert long-term detrimental effects on individuals trajectory of cognition.

Region-Specific Iron Measured by MRI as a Biomarker for Parkinson’s Disease

The identification of sensitive and specific biomarkers for Parkinson’s disease (PD) poses an important clinical challenge. A potential biomarker for early diagnosis and disease monitoring of PD is region-specific iron. Iron accumulation in the substantia nigra pars compacta is considered a main characteristic of PD. However, questions remain, such as the relationship between nigral iron and clinical indices of PD (motor impairment or disease duration). Further, previous studies have suggested the influence of iron on other nuclei. Iron quantification using magnetic resonance imaging (MRI) allows for studies of the relationship between regional iron and clinical symptoms in vivo. Thus, in this review we discuss the following topics: the technological development of MRI in measuring brain iron, nigral iron as a potential marker for PD in both clinical and prodromal stages, other influences of regional iron on PD, and clinical translation and future perspectives.

Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimers disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p <  0.05; r = 0.65, p <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

Alteration of regional homogeneity and white matter hyperintensities in amnestic mild cognitive impairment subtypes are related to cognition and CSF biomarkers

Amnestic mild cognitive impairment can be further classified as single-domain aMCI (SD-aMCI) with isolated memory deficit, or multi-domain aMCI (MD-aMCI) if memory deficit is combined with impairment in other cognitive domains. Prior studies reported these clinical subtypes presumably differ in etiology. Thus, we aimed to explore the possible mechanisms between different aMCI subtypes by assessing alteration in brain activity and brain vasculature, and their relations with CSF AD biomarkers. 49 healthy controls, 32 SD-aMCI, and 32 MD-aMCI, who had undergone structural scans, resting-state functional MRI (rsfMRI) scans and neuropsychological evaluations, were identified. Regional homogeneity (ReHo) was employed to analyze regional synchronization. Periventricular white matter hyperintensities (PWMH) and deep WMH (DWMH) volume of each participant was quantitatively assessed. AD biomarkers from CSF were also measured. SD-aMCI showed decreased ReHo in medial temporal gyrus (MTG), and increased ReHo in lingual gyrus (LG) and superior temporal gyrus (STG) relative to controls. MD-aMCI showed decreased ReHo, mostly located in precuneus (PCu), LG and postcentral gyrus (PCG), relative to SD-aMCI and controls. As for microvascular disease, MD-aMCI patients had more PWMH burden than SD-aMCI and controls. Correlation analyses indicated mean ReHo in differenced regions were related with memory, language, and executive function in aMCI patients. However, no significant associations between PWMH and behavioral data were found. The Aβ level was related with the ReHo value of STG in SD-aMCI. MD-aMCI displayed different patterns of abnormal regional synchronization and more severe PWMH burden compared with SD-aMCI. Therefore aMCI is not a uniform disease entity, and MD-aMCI group may show more complicated pathologies than SD-aMCI group.

Longitudinal Alterations of Local Spontaneous Brain Activity in Parkinson’s Disease

Abstract We used resting-state fMRI to evaluate longitudinal alterations in local spontaneous brain activity in Parkinson’s disease (PD) over a 2-year period. Data were acquired from 23 PD patients at baseline and follow-up, and 27 age- and sex-matched normal controls. Regional homogeneity (ReHo) and voxel-based-morphometry (VBM) were used to identify differences in local spontaneous brain activity and grey matter volume. With disease progression, we observed a progressive decrease in ReHo in the sensorimotor cortex, default-mode network, and left cerebellum, but increased ReHo in the supplementary motor area, bilateral temporal gyrus, and hippocampus. Moreover, there was a significant positive correlation between the rates of ReHo change in the left cerebellum and the rates of change in the Unified Parkinson’s Disease Rating Scale-III scores. VBM revealed no significant differences in the grey matter volume among the three sets of acquisitions. We conclude that ReHo may be a suitable non-invasive marker of progression in PD.

Disrupted Functional Connectivity of Basal Ganglia across Tremor-Dominant and Akinetic/Rigid-Dominant Parkinson’s Disease

It is well known that disruption of basal ganglia function generates the motor symptoms in PD, however, these are presented in a heterogeneous manner; patients can be divided into tremor-dominant and akinesia/rigidity-dominant subtypes. To date, it is unknown if these differences in the motor symptoms could be explained by differences on the functional connectivity of basal ganglia with specific brain regions. In this study, we aimed to explore the alterations of the network-based and global functional connectivity linking to basal ganglia between the PD-TD and PD-AR patients. One hundred and six PD patients and 52 normal controls were recruited. According to the subscales of UPDRS motor scale, PD patients were divided into the PD-TD (n = 57) and PD-AR (n = 49) subtypes. We performed independent component analysis to identify basal ganglia network (BGN) involving connected brain regions having coactivation with basal ganglia. Eigenvector centrality mapping were processed and the eigenvector centrality in the subcortical component of BGN including the bilateral caudate nuclei, putamen, thalami and pallidum were extracted to measure the global connectivity. Compared with controls, whole PD patients or PD subtypes showed decreases of functional connectivity within the subcortical component of BGN, e.g., thalamus, pallidum and putamen. Compared with controls, decreased functional connectivity of precuneus and amygdala with basal ganglia was observed in the PD-TD while that of occipital lobule and precuneus was observed in the PD-AR. Compared with the PD-TD, significantly decreased functional connectivity between occipital lobule and cerebellum posterior lobule and basal ganglia was observed in the PD-AR, and such connectivity had positive correlations with tremor and negative correlations with akinesia/rigidity. We also observed enhanced global connectivity in the caudate nucleus and thalamus in the PD subtypes compared with controls. In conclusion, PD patients independent of motor subtypes consistently express similar alterations of functional connectivity within the subcortical component of BGN including network-based connectivity and global connectivity. Functional connectivity of cerebellum posterior lobule and occipital lobule with basal ganglia play important roles in the modulation of parkinsonian motor symptoms.

Increased thalamic centrality and putamen–thalamic connectivity in patients with parkinsonian resting tremor

Evidence has indicated a strong association between hyperactivity in the cerebello‐thalamo‐motor cortical loop and resting tremor in Parkinsons disease (PD). Within this loop, the thalamus serves as a central hub based on its structural centrality in the generation of resting tremor. To study whether this thalamic abnormality leads to an alteration at the whole‐brain level, our study investigated the role of the thalamus in patients with parkinsonian resting tremor in a large‐scale brain network context.