Tao Feng

Neural correlates underlying micrographia in Parkinson’s disease

Micrographia is a common symptom in Parkinsons disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks.

Heterogeneity among patients with Parkinson's disease: cluster analysis and genetic association.

The clinical heterogeneity of Parkinsons disease (PD) reveals the presence of several PD subtypes. The objectives of this study were to identify PD subtypes using cluster analysis (CA) and to determine the association between the subtypes and the polymorphisms in LRRK2 (G2385R and R1628P) and GBA (L444P) genes. A k-means CA of demographics, disease progression, motor and non-motor symptoms was performed from 1,510 Chinese PD patients from the Chinese National Consortium on Neurodegenerative Diseases. Pearson correlation analysis was performed to eliminate uninformative characteristics. Blood samples from 852 patients were obtained for genetic analysis of LRRK2 and GBA. Genotypic associations between various subtypes and genetic variants were examined using chi-square test. We identified four different subtypes: subtype 1 was non-tremor dominant (NTD, n=469; 31.1%); subtype 2 had a rapid disease progression with late onset (RDP-LO, n=67; 4.4%); subtype 3 had benign pure motor characteristics (BPM, n=778; 51.5%) without non-motor disturbances; and subtype 4 was tremor dominant with slow disease progression (TD-SP, n=196; 13.0%). Subtypes 1, 2, and 4 had similar mean age of onset. No associations were identified between polymorphisms in LRRK2 (R1628P) and GBA (L444P) genes and the four subtypes (P>0.05).

Impaired brain network architecture in newly diagnosed Parkinson’s disease based on graph theoretical analysis

BACKGROUND Resting state functional magnetic resonance imaging (rs-fMRI) has been applied to investigate topographic structure in Parkinsons disease (PD). Alteration of topographic architecture has been inconsistent in PD AIM: To investigate the network profile of PD using graph theoretical analysis. METHOD Twenty six newly diagnosed PD and 19 age- and gender- matched healthy controls (HC) were included in our analysis. Small-world profile and topographic profiles (nodal degree, global efficiency, local efficiency, cluster coefficient, shortest path length, betweenness centrality) were measured and compared between groups, with age and gender as covariates. We also performed correlation analysis between topographic features with motor severity measured by UPDRS III. RESULTS Small-world property was present in PD. Nodal degree, global efficiency, local efficiency and characteristic path length consistently revealed disruptive sensorimotor network, and visual network to a less degree in PD. By contrast, default mode network (DMN) and cerebellum in PD showed higher nodal degree, global efficiency and local efficiency, and lower characteristic path length. Global and local efficiency in the midbrain was higher in PD excluding substantia nigra. PD group also exhibited lower cluster coefficient in the subcortical motor network (thalamus and caudate nucleus). No significant correlation was found between topographic properties and motor severity. CONCLUSION PD exhibited disruptive sensorimotor and visual networks in early disease stage. DMN, a certain areas in the cerebellum and midbrain may compensate for disruptive sensorimotor and visual network in PD. Disruptive network architecture may be an early alteration of PD pathophysiology but may not serve as a valid biomarker yet.

Functional Connectivity of Vim Nucleus in Tremor- and Akinetic-/Rigid-Dominant Parkinson's Disease

The aim of this study was to investigate the involvement of the ventral intermediate nucleus of thalamus (Vim) in the tremor‐ and akinetic‐/rigid‐related networks in Parkinsons disease (PD).

Resting-state functional connectivity of subthalamic nucleus in different Parkinson's disease phenotypes

Previous studies showed that the subthalamic nucleus (STN) plays a crucial role in Parkinsons disease (PD) pathophysiology. During rest, PD phenotypes exhibit different STN functional connectivity. STN functional connectivity was examined in 31 PD patients [12 tremor-dominant (TD) and 19 posture instability gait difficulty (PIGD)] and 22 healthy controls (HC). Compared with controls and PIGD patients, the TD patients exhibited higher functional connectivity between the bilateral STN and the left cerebellar anterior lobe. Compared with the TD and HC groups, in the PIGD subgroup functional connectivity was lower between the left putamen and the STN, as well as between the pons and the STN. In the PIGD subgroup, functional connectivity was greater between the STN and bilateral occipital lobe, which positively correlated with PIGD scores in PD patients. Additionally, STN-cerebellum connectivity positively correlated with the tremor score, and STN-putamen connectivity negatively correlated with the PIGD score in PD patients. PD subtypes with distinguished STN functional connectivity might explain the various pathophysiological mechanisms in tremor and gait disorders. Increased coupling between the STN and cerebellum might underlie the neural substrate of PD tremors. Lower functional connectivity between the STN and putamen might underpin PD gait and posture disturbances, while higher functional connectivity between the STN and visual cortex might play a compensatory role.

Quantitative assessment of cerebral gray matter density change in progressive supranuclear palsy using voxel based morphometry analysis and cerebral MR T1-weighted FLAIR imaging.

PURPOSE To investigate the gray matter (GM) atrophy in Progressive supranuclear palsy (PSP) using T1-weighted Fluid-Attenuated Inversion Recovery (FLAIR) images based on voxel based morphometry (VBM) method. MATERIALS AND METHODS In this study, we firstly modified the conventional VBM method to make it can process the T1-weighted FLAIR brain images. Then, we used this method on the 24 PSP patients and 23 healthy age- and sex-matched control subjects to find the local gray matter density changes of PSP patients. RESULTS Compared with healthy controls, GM reductions of PSP patients mainly located in the thalamus, basal ganglia, pons, midbrain, insular cortex, frontal cortex, temporal lobe, cerebellum, cingulate cortex and hippocampus. CONCLUSION We used the modified VBM technique into T1 FLAIR data to study the brain gray matter atrophy in PSP, and found some new atrophy areas, including pallidum, middle and posterior cingulum, lingual, fusiform gyrus and the post part of inferior temporal gyrus. These areas have not been described in the former VBM studies, but they revealed abnormity in the pathologic and other studies on PSP. Our results might be expected to provide significant underlining neurology information and diagnostic value for PSP.

Effective network of deep brain stimulation of subthalamic nucleus with bimodal positron emission tomography/functional magnetic resonance imaging in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) has become an effective treatment strategy for patients with Parkinsons disease. However, the biological mechanism underlying DBS treatment remains poorly understood.

Frequency-dependent effects of subthalamic deep brain stimulation on motor symptoms in Parkinson’s disease: a meta-analysis of controlled trials

This study aims to investigate how the frequency settings of deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) influence the motor symptoms of Parkinson’s disease (PD). Stimulation with frequencies less than 100 Hz (mostly 60 or 80 Hz) is considered low-frequency stimulation (LFS) and with frequencies greater than 100 Hz (mostly 130 or 150 Hz) is considered high-frequency stimulation (HFS). We conducted a comprehensive literature review and meta-analysis with a random-effect model. Ten studies with 132 patients were included in our analysis. The pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, −1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, −1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, −4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, −1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS.

Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson's disease

INTRODUCTION Glucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinsons disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants. METHODS The participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender. RESULTS Total 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers. CONCLUSIONS The prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD.

Alpha-synuclein in erythrocyte membrane of patients with multiple system atrophy: A pilot study

BACKGROUND Multiple system atrophy(MSA) is a neurodegenerative disease characterized by intracellular α-synuclein deposits. There is an unmet need for blood-based biomarkers to diagnose MSA. Our previous studies have reported elevated α-synuclein levels in erythrocytes of MSA patients. However, α-synuclein protein in the membrane and cytoplasm of erythrocytes in MSA have not been investigated. METHODS The membrane and cytoplasm were extracted from erythrocytes in 77 patients with MSA and 133 healthy controls. Levels of total and oligomeric α-synuclein were detected using Electrochemiluminescence assays. The correlations between α-synuclein levels and clinical characteristics were explored in MSA group. The diagnostic value of erythrocyte α-synuclein for MSA was determined by Receiver operator characteristic curve. RESULTS α-synuclein levels in the erythrocyte membrane were significantly elevated in MSA patients compared with the healthy controls (total α-synuclein, p = 0.003; oligomeric α-synuclein/total α-synuclein, p = 0.033; oligomeric α-synuclein/protein, p < 0.001). The combination of total and oligomeric α-synuclein levels in erythrocyte membrane could efficiently distinguish MSA from healthy controls (sensitivity of 79.2%; specificity of 69.2%; area under the curve: 0.771). In contrast, no significant difference was found in erythrocyte cytoplasm α-synuclein levels. In the subgroup of 48 patients with probable MSA, there was a weakly negative correlation between oligomeric α-synuclein/protein in erythrocyte membrane and disease duration (r = -0.336; p = 0.009). CONCLUSION Our pilot study suggests that the membrane fraction of α-synuclein levels in erythrocyte were elevated in patients with MSA, and these levels may be decreased with the development of disease.