Inter-cortical modulation from premotor to motor plasticity.

KEY POINTS: Synaptic plasticity is involved in daily activities but abnormal plasticity may be deleterious. In this study, we found that motor plasticity could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Such changes in motor plasticity were associated with reduced learning of a simple motor task. We postulate that the premotor cortex adjusts the amount of motor plasticity to modulate motor learning through heterosynaptic metaplasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network, a concept that could be employed to intervene in diseases with abnormal plasticity. ABSTRACT: Primary motor cortex (M1) plasticity is known to be influenced by the excitability and prior activation history of M1 itself. However, little is known about how its plasticity is influenced by other areas of the brain. In the present study on humans of either sex who were known to respond to theta burst stimulation from previous studies, we found plasticity of M1 could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Motor plasticity was distorted and disappeared 30 min and 120 min, respectively, after premotor excitability was suppressed. Further evaluation revealed that such changes in motor plasticity were associated with impaired learning of a simple motor task. We postulate that the premotor cortex modulates the amount of plasticity within M1 through heterosynaptic metaplasticity, and that this may impact on learning of a simple motor task previously shown to be directly affected by M1 plasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network. Furthermore, such concepts could be translated into therapeutic approaches for diseases with aberrant plasticity.

The Unraveled Link Between Antiviral Therapy and Heart Failure Hospitalization in Chronic Hepatitis C Virus Infection　- A Nationwide Cohort Study.

BACKGROUND: Although hepatitis C virus (HCV) is a known risk factor for cardiovascular disease, whether antiviral therapy (AVT) can reduce heart failure (HF) hospitalizations is unknown.Methods and Results:In this population-based cohort study, we used data from the Taiwan National Health Insurance Research Database to evaluate the effect of interferon-based therapy (IBT) on cardiovascular events in patients with chronic HCV infection. Clinical outcomes evaluated included HF hospitalizations; a composite of acute myocardial infarction, ischemic stroke, and peripheral artery disease; all-cause death; and cardiovascular death. Of 83,229 eligible patients with chronic HCV infection, we compared 16,284 patients who received IBT with untreated subjects after propensity score matching. Patients who received IBT were less likely to be hospitalized for HF compared with untreated subjects (incidence density.ID, 0.9 vs. 1.5 events per 103person-years; hazard ratio.HR, 0.58; 95% confidence interval.CI, 0.42-0.79; P=0.001). Compared with untreated subjects, the treated group had significantly lower risk of composite vascular events (ID, 3.7 vs. 5.0 events per 103person-years; P<0.001), all-cause death (ID, 5.6 vs. 17.2 events per 103person-years; P<0.001), and cardiovascular death (ID, 0.2 vs. 0.6 events per 103person-years; P=0.001). CONCLUSIONS: AVT for chronic HCV infection might offer protection against HF hospitalizations, critical vascular events, and cardiovascular death beyond known beneficial effects.

Add-on neurological benefits of antiviral therapy in HCV patients with chronic kidney disease - a nationwide cohort study.

BACKGROUND: Hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) have rarely been studied because they rarely accept interferon-based therapy (IBT) and have been difficult to follow up. We investigated long-term outcomes of IBT on the population. METHODS: This population-based cohort study used the Taiwan National Health Insurance Research Database as its data source. HCV patients diagnosed with CKD between Jan. 1, 2003, and Dec. 31, 2013, were selected. They were then divided into two groups based on whether they had undergone IBT. All-cause mortality, acute myocardial infarction (AMI), ischemic stroke (IS), hemorrhagic stroke, and new-onset dialysis were evaluated using a Cox proportional hazard regression analysis after propensity score matching. RESULTS: We enrolled 9872 HCV patients with CKD: 1684 patients in the treated cohort and 8188 patients in the untreated cohort. The annual incidence of all-cause mortality (19.00 vs. 42.89 events per 1000 person-years; p < 0.001) and the incidences of hemorrhagic stroke (1.21 vs. 4.19 events per 1000 person-years; p = 0.006) were lower in the treated cohort. New-onset dialysis was also lower in the treated cohort (aHR: 0.31; 95% CI: 0.20-0.48; p < 0.001). CONCLUSION: Antiviral therapy might provide protective benefits on all-cause mortality, hemorrhagic stroke, and new-onset dialysis in HCV-infected patients with CKD.

Alterations of diffusion tensor MRI parameters in the brains of patients with Parkinson's disease compared with normal brains: possible diagnostic use.

OBJECTIVES: To investigate the diagnostic performance of diffusion tensor imaging in patients with Parkinson's disease (PD). METHODS: We examined a total of 126 PD patients (68 males/58 females, mean age: 62.0 ±7.6 years) and 91 healthy controls (43 males/48 females, mean age: 59.8 ±7.2 years). Images were acquired on a 3 Tesla magnetic resonance scanner. The Camino software was used to normalize and parcellate diffusion-weighted images into 90 cerebral regions based on the automatic anatomical labelling template. The minimum, median, and maximum values of the mean/radial/axial diffusivity/fractional anisotropy were determined. The diagnostic performance was assessed by receiver operating characteristic analysis. The associations of imaging parameters with disease severity were tested using Pearson's correlation coefficients after adjustment for disease duration. RESULTS: Compared with healthy controls, PD patients showed increased diffusivity in multiple cortical regions that extended beyond the basal ganglia. An area under curve of 85 % was identified for the maximum values of mean diffusivity in the ipsilateral middle temporal gyrus. The most significant intergroup difference was 26.8 % for the ipsilateral inferior parietal gyrus. CONCLUSION: The measurement of water diffusion from the parcellated cortex may be clinically useful for the assessment of PD patients. KEY POINTS: • Increased diffusivity was identified in multiple cortical regions of Parkinson's disease patients. • The area under the receiver operating curve was 85 % in the middle temporal gyrus. • The ipsilateral inferior parietal gyrus showed the most significant change.

The impact of low-frequency stimulation of subthalamic region on self-generated isometric contraction in patients with Parkinson's disease.

Growing evidence suggests that spontaneous oscillatory low-frequency synchronization in the subthalamic nuclei (STN) may modulate motor performance in patients with Parkinson's disease (PD). To explore this in more detail, 15 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both STN were stimulated bilaterally at 5, 10, 20, 50 and 130 Hz and the effects of the DBS on self-initiated isometric elbow flexion (FLEX) and finger pinch (PINCH) were compared to performance without DBS. Baseline performance was very much impaired. Peak force was significantly greater during 130 and 10 Hz stimulation when compared to no stimulation in both tasks. Cumulative sums of the changes in mean rising force and peak force in the two tasks upon stimulation at 10 and 20 Hz demonstrated that patients improved their performance on stimulation, except for those with the best performance off stimulation who deteriorated with stimulation at 20 Hz. Thus, no effect was detected with 20 Hz stimulation at the group level. The current study highlights the need to consider the baseline performance of a subject in a given task when determining the effects of low-frequency STN stimulation in PD patients. It also demonstrates that stimulation at 10 Hz can improve motor function in subjects with poor baseline function.

Venous Thromboembolism and Critical Limb Events in Patients with Atrial Fibrillation: A Nationwide Population-Based Cohort Study.

Little is known about whether venous thromboembolism (VTE) causes worse critical limb events in populations with atrial fibrillation (AF). A retrospective cohort study using claims data from Taiwan's National Health Insurance program between 2001 and 2013 compared AF patients with or without VTE. Outcomes were percutaneous transluminal angioplasty (PTA), amputation, systemic thromboembolism, all-cause mortality, cardiovascular death, ischemic stroke, and acute myocardial infarction. Patients (n = 316,817) with newly diagnosed AF were analyzed; of those, 2514 (0.79%) had VTE history. After inverse probability of treatment weighting, a history of VTE was significantly associated with higher risks of PTA (3.3 vs 2.2%; subdistribution hazard ratio [SHR] 1.47; 95% confidence interval [CI] 1.17-1.84); above knee amputation (0.7 vs 0.3%; HR 2.15; 95% CI 1.10-4.21); systemic thromboembolism (5.8 vs 3.9%; SHR 1.48; 95% CI 1.21-1.80); all-cause mortality (53 vs 46.4%; HR 1.20, 95% CI 1.12-1.29); and cardiovascular death (34.8 vs 29.4%; HR 1.25, 95% CI 1.14-1.36). In conclusion, VTE might increase the risk of critical lower limb events (PTA and above-knee amputation), systemic thromboembolism, and mortality in the AF population. However, current data cannot confirm a causal relationship between VTE and clinical outcomes in this population.

Parkinson disease: diagnostic utility of diffusion kurtosis imaging.

PURPOSE: To examine the usefulness of diffusion kurtosis imaging for the diagnosis of Parkinson disease (PD). MATERIALS AND METHODS: Examinations were performed with the understanding and written consent of each subject, with local ethics committee approval, and in compliance with national legislation and Declaration of Helsinki guidelines. Diffusion-weighted magnetic resonance imaging was performed in 30 patients with idiopathic PD (mean age, 64.5 years ± 3.4 [standard deviation]) and 30 healthy subjects (mean age, 65.0 years ± 5.1). Mean kurtosis, fractional anisotropy, and mean, axial, and radial diffusivity of the basal ganglia were compared between the groups. Disease severity was assessed by using Hoehn and Yahr staging and the motor section of the Unified Parkinson's Disease Rating Scale (mean scores, 2.0 and 33.6, respectively). Receiver operating characteristic (ROC) analysis was used to compare the diagnostic accuracies of the indexes of interest. Pearson correlation coefficient analysis was used to correlate imaging findings with disease severity. RESULTS: Mean kurtosis in the putamen was higher in the PD group (0.93 ± 0.15) than in the control group (0.71 ± 0.09) (P < .000416). The area under the ROC curve (AUC) was 0.95 for both the ipsilateral putamen and the ipsilateral substantia nigra. The mean kurtosis for the ipsilateral substantia nigra had the best diagnostic performance (mean cutoff, 1.10; sensitivity, 0.92; specificity, 0.87). In contrast, AUCs for the tensor-derived indexes ranged between 0.43 (axial and radial diffusivity in substantia nigra) and 0.65 (fractional anisotropy in substantia nigra). CONCLUSION: Diffusion kurtosis imaging in the basal ganglia, as compared with conventional diffusion-tensor imaging, can improve the diagnosis of PD.

Reversal of plasticity-like effects in the human motor cortex.

A number of experiments in animals have shown that successful induction of plasticity can be abolished if an individually ineffective intervention is given shortly afterwards. Such effects are termed depotentiation/de-depression. These effects contrast with metaplasticity/homeostatic plasticity in which pretreatment of the system with one protocol modulates the response to a second plasticity-inducing protocol. Homeostatic plasticity maintains the balance of plasticity in the nervous system at a stable level whereas depotentiation/de-depression abolishes synaptic plasticity that has just occurred in order to prevent ongoing learning. In the present study, we developed novel protocols to explore the reversal of LTP- and LTD-like effects in healthy conscious humans based on the recently developed theta burst form of repetitive transcranial magnetic stimulation (TBS). The potentiation effect induced by intermittent TBS (iTBS) was completely erased by a short form of continuous TBS (cTBS150) given 1 min after iTBS, whereas the depressive effect of continuous TBS (cTBS) was successfully abolished by a short form of iTBS (iTBS150). The reversal was specific to the nature of the second protocol and was time dependent since it was less effective when the intervention was given 10 min after induction of plasticity. All these features are compatible with those of depotentiation and de-depression demonstrated in animal studies. The development of the present protocols would be helpful to study the physiology of the reversal of plasticity and learning and to probe the abnormal depotentiation/de-depression shown in animal models of neurological diseases (e.g. Parkinson's disease with dyskinesia, dystonia and Huntingon's disease).

Microstructural changes in patients with progressive supranuclear palsy: a diffusion tensor imaging study.

PURPOSE: To determine whether progressive supranuclear palsy (PSP) is associated with specific diffusion tensor imaging (DTI) patterns of diffusivity, anisotropy, and coherence in functionally relevant brain areas. MATERIALS AND METHODS: In all, 17 PSP patients and 17 controls were scanned using a 3 T magnetic resonance imaging (MRI) scanner. Patients were assessed in the off-medication condition using the Hoehn and Yahr staging and the United Parkinson's Disease Rating Scale, motor subscale (UPDRS-III). Diffusion information were analyzed in relation to disease severity and subtypes. RESULTS: Numerous changes in diffusion properties were identified in the subcortical areas. In the midbrain, fractional anisotropy (FA) decreased and MD (mean diffusivity) increased with disease progression. UPDRS-III scores correlated positively with both FA in the caudate and MD in the pons. DTI analysis of disease subtypes demonstrated significant differences between PSP-Parkinsonism and Steele-Richardson-Olszewski syndrome in axial diffusivity values in the putamen and globus pallidus, as well as in intervoxel diffusion coherence values in the middle cerebellar peduncle. CONCLUSION: Our findings, cautiously interpreted, demonstrate the advantage of using a functional imaging technique to aid in the specificity of defining more precisely the pathological processes taking place in white and gray matter regions in PSP.

Nonmotor symptoms of 820 Taiwanese patients with Parkinson's disease: an exploratory-comparative study.

INTRODUCTION: Nonmotor symptoms (NMSs) severely affect the daily quality of life of patients with Parkinson's disease (PD). Although many studies have documented the clinical characteristics of NMSs in PD patients, some issues remain unaddressed. The severity and gender distribution of NMSs in Asian and the Western patients differ. The correlations between clinical characteristics and NMS manifestations remain unclear. We studied these relationships in a large cohort of Taiwanese PD patients. METHODS: Patients with PD were recruited from the outpatient clinic of a tertiary medical center and evaluated with standardized assessment protocols, including the NonMotor Symptoms Scale (NMSS), Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, Mini-Mental Status Examination, and Montreal Cognitive Assessment. RESULTS: Among 820 patients enrolled, 41.8% were female. The prevalence of the NMSs was 96.5%, with attention/memory (79.51%) being the most frequently involved domain. The mean severity score on the NMSS was 36.48 ± 34.30. Male patients reported higher NMS prevalence and severity than female patients, mostly in the gastrointestinal tract and urinary domains. We found that the severity of NMSs was correlated with disease duration, UPDRS Part III score, and H&Y stage. CONCLUSION: Although they exhibited similar NMS prevalence, Taiwanese PD patients reported less intense NMSs compared with those reported by Western patients. Furthermore, the NMS items our patients emphasized and gender discrepancies were distinct from those in Western studies.

Effect of initiating statin therapy on long-term outcomes of patients with dyslipidemia after intracerebral hemorrhage.

BACKGROUND AND AIMS: Intracerebral hemorrhage (ICH) has a higher mortality than ischemic stroke. Statin is beneficial for stroke, but high potency statin treatment has been associated with the risk of hemorrhagic stroke. The aim of this study was to assess the impact of initiating statin therapy after ICH on cardiovascular outcomes. METHODS: Dyslipidemic patients were retrieved from the ICH population from the National Health Insurance Research Database in Taiwan. We retrospectively compared patients prescribed with and without statin treatment after ICH. Outcomes of interest were mortality, myocardial infarction, ischemic stroke, and hemorrhagic stroke during 5 years of follow-up. RESULTS: Of 17,980 adult patients with ICH and dyslipidemia, 8927 were eligible for analysis over the study period, including 1613 patients receiving statin therapy and 7314 patients not taking statins. After propensity score matching, the mean age was 61.2 ±â€¯12.2 years in the statin group and 61.6 ±â€¯13.0 years in the non-statin group. Hypertension was dominant, followed by diabetes mellitus, and the mean estimated NIHSS score was 12.9. The patients who received statin therapy were associated with lower risks of all-cause mortality (12.7% vs. 21.3%; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.45-0.65), cardiovascular death (4.0% vs. 7.1%; HR, 0.54; 95% CI, 0.39-0.75) and ICH (5.4% vs. 8.5%; HR, 0.62; 95% CI, 0.46-0.83) compared to those who did not receive statins. CONCLUSIONS: Initiating statin therapy after ICH was associated with a decreased risk of recurrent ICH and mortality for dyslipidemia patients.

Association of Antiviral Therapy With Risk of Parkinson Disease in Patients With Chronic Hepatitis C Virus Infection.

IMPORTANCE: Epidemiologic evidence suggests that hepatitis C virus (HCV) could be a risk factor for Parkinson disease (PD), but treatment for HCV infection has never been considered in these studies; hence, the association between antiviral therapy and PD incidence has remained unclear. Understanding this association may help in developing strategies to reduce PD occurrence. OBJECTIVE: To identify the risk of PD development in patients with HCV infection receiving antiviral treatment and in patients not receiving this treatment. DESIGN, SETTING, AND PARTICIPANTS: This cohort study obtained claims data from the Taiwan National Health Insurance Research Database. Adult patients with a new HCV diagnosis with or without hepatitis per International Classification of Diseases, Ninth Revision, Clinical Modification codes and anti-PD medications from January 1, 2003, to December 31, 2013, were selected for inclusion. After excluding participants not eligible for analysis, the remaining patients (n = 188 152) were categorized into treated and untreated groups according to whether they received antiviral therapy. Propensity score matching was performed to balance the covariates across groups for comparison of main outcomes. This study was conducted from July 1, 2017, to December 31, 2017. MAIN OUTCOMES AND MEASURES: Development of PD was the main outcome. A Cox proportional hazards regression model was used to compare the risk of PD, and the hazard ratio (HR) was calculated at 1 year, 3 years, and 5 years after the index date and at the end of the cohort. RESULTS: A total of 188 152 patients were included in the analysis. An equal number (n = 39 936) and comparable characteristics of participants were retained in the treated group (with 17 970 female [45.0%] and a mean [SD] age of 52.8 [11.4] years) and untreated group (with 17 725 female [44.4%] and a mean [SD] age of 52.5 [12.9] years) after matching. The incidence density of PD was 1.00 (95% CI, 0.85-1.15) in the treated group and 1.39 (95% CI, 1.21-1.57) per 1000 person-years in the untreated group. The advantage of antiviral therapy reached statistical significance at the 5-year follow-up (HR, 0.75; 95% CI, 0.59-0.96), and this advantage continued to increase until the end of follow-up (HR, 0.71; 95% CI, 0.58-0.87). CONCLUSIONS AND RELEVANCE: Evidence suggested that the PD incidence was lower in patients with chronic HCV infection who received interferon-based antiviral therapy; this finding may support the hypothesis that HCV could be a risk factor for PD.

Antiviral therapy reduces risk of haemorrhagic stroke in patients with HCV infection: a nationwide cohort study.

BACKGROUND: The tendency for haemorrhagic stroke in patients with chronic HCV infection has emerged recently but the finding may be confounded by comorbidities. Proving the causality between HCV infection and haemorrhagic stroke is mandatory. Our study was designed to investigate the incidence of intracranial haemorrhage in HCV-infected patients with and without treatment. METHODS: In the 11-year and population-based retrospective study, we acquired data from the Taiwan National Health Insurance Research Database. The patients with major comorbidities were excluded and 97,198 HCV-infected patients were included for analysis. Treated and untreated cohorts were matched with propensity score to make the confounding factors in two groups comparable. Cox proportional hazard regression analysis was performed to evaluate the hazard ratio of haemorrhagic stroke in the cohorts. We applied survival analysis to compare the cumulative incidence of outcome events between the two cohorts. RESULTS: After matching, the incidence density (ID) of haemorrhagic stroke in the untreated cohort is significantly higher than in the treated cohort (ID: 1.0 versus 0.6 events per 1,000 person-years; P=0.0014). The adjusted hazard ratio (aHR) of haemorrhagic stroke is significantly reduced in the treated group (P<0.05). Cumulative incidence of haemorrhagic stroke is significantly lower in the treated group than in the untreated group (P=0.013). CONCLUSIONS: The study demonstrates that antiviral therapy significantly reduces the events of intracranial haemorrhage in HCV-infected patients and consolidates the novel concept that chronic HCV infection is a risk factor for haemorrhagic stroke.

Indirect Targeting of Subthalamic Deep Brain Stimulation Guided by Stereotactic Computed Tomography and Microelectrode Recordings in Patients With Parkinson's Disease.

Objective: Magnetic resonance imaging fusion techniques guided by frame-based stereotactic computed tomography and microelectrode recordings are widely used to target the subthalamic nucleus. However, MRI is not always available. The aim of this study was to determine whether the indirect targeting of the subthalamic nucleus for deep brain stimulation using frame-based stereotactic computed tomography and microelectrode recording guidance in patients with advanced idiopathic Parkinson's disease was an effective and safe treatment and to determine the factors that contributed to outcome. Methods: Thirty-four consecutive patients with Parkinson's disease who were treated from 2010 to 2012 were enrolled in this retrospective cohort study. The patients were assessed with the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III) and other clinical profiles peri- and post-operatively. The horizontal and vertical distances between the midpoint of the head frame and the brain midline at the septum pellucidum level and the upper edge of the bilateral lens, respectively, on a thin-section brain computed tomography scan were defined as the horizontal and vertical deviations, respectively. Results: After the deep brain stimulation surgery, the patients' UPDRS-III scores improved 48 ± 2.8% (range, 20-81%) compared to the patients' baseline off-levodopa scores. No surgery-associated complications were found. The mean recorded length difference of the subthalamic nucleus between the initial and final single microelectrode recording trajectories was 5.37 ± 0.16 mm (range, 3.99-7.50). Multiple linear regression analyses revealed that the increased lengths of the vertical (regression coefficient [B]: -0.0626; 95% confidence interval [CI]: -0.113 to -0.013) and horizontal deviations (B: -0.0497; 95% CI: -0.083 to -0.017) were associated with less improvement in the patients' UPDRS scores. Conclusion: These results showed that the indirect targeting of the subthalamic nucleus for deep brain stimulation using frame-based stereotactic computed tomography and microelectrode recording guidance in patients with advanced idiopathic Parkinson's disease was effective and safe. Greater symmetry of the head frame fixation resulted in better outcomes of the deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease, especially when the horizontal deviation was 2 mm or less and the vertical deviation was 1 mm or less.

Sleep disturbances in Taiwanese patients with Parkinson's disease.

INTRODUCTION: Sleep disturbance is a common nonmotor symptom of Parkinson's disease (PD) and strongly affects patients' quality of life. The relationship between excessive daytime sleepiness (EDS) and nighttime problems remains uncertain. Arguments persist regarding the risk factors for sleep disturbance among patients with PD. Furthermore, the prevalence of EDS appears to be lower in Asian countries. Herein, we conducted the study to describe the characteristics of sleep problems in a sample of Taiwanese PD patients and delineate the difference with reported sleep disturbances in Caucasian PD patients from the literature. METHODS: Patients with PD were recruited from the outpatient clinic of a tertiary medical center and were evaluated using standardized assessment protocols, including the Parkinson's Disease Sleep Scale (PDSS), the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and 39-Item Parkinson's Disease Questionnaire (PDQ-39). RESULTS: A total of 225 patients with PD were recruited. The mean age of patients with PD was 65.7 years old and the mean disease duration was 8.18 years. Among the patients, 53.8% were defined as poor sleepers (PSQI > 5) and 26.3% had EDS. Seventy-one percent of the poor sleepers used hypnotic medications. The poor sleepers were worse in the scores of Unified Parkinson's Disease Rating Scale (UPDRS), PDSS, and the PDQ-39, and received higher levodopa daily dosage. A PDSS score of <126 indicate that a patient with PD was a poor sleeper. EDS was positively correlated with advanced Hoehn and Yahr stages and use of dopamine agonists but not with levodopa daily dosage and levodopa equivalent daily dosage. CONCLUSIONS: Taiwanese patients with PD had a lower prevalence of EDS compared with the literatures reported in Caucasian patients. We identify and suggest that PDSS total score, rather than subcategory items, should be used to predict poor sleep among patients with PD.

Cortical damage in the posterior visual pathway in patients with sialidosis type 1.

In order to identify the cortical changes in patients with Sialidosis type 1, diffusion tensor imaging and resting state fMRI were acquired from 11 patients and 11 sex/age matched normal controls after clinical evaluations. The neuroimages from each participant were normalized and parcellated according to the Automatic Anatomical Labeling. Both the mean diffusivity and the corresponding functional connectivity were calculated from each cortical region. The white matter tract integrity was examined. The difference between patients and controls was examined using Student's t-test and between patients with either homozygous or heterozygous mutations by Mann-Whitney U test, both at a threshold of 0.05. Increased mean diffusivity throughout the brain can be noticed in the patients, together with a compromised white matter tracts integrity. The most severely affected cortical regions are in the occipital lobe. Decreased functional connectivity was from the temporal and occipital lobes to the hippocampus and parahippocampus. In contrast, connectivity from thalamus was enhanced. Diffused cortical atrophy with posterior focal lesions was noticed. We concluded that MRI observed functional changes in the posterior cortical pathways in the patients with Sialidosis. The observation might be related to the cortical blindness due to an altered neural network and a compromised visual pathway in the patients.

Increased Rab35 expression is a potential biomarker and implicated in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is the second common neurodegenerative disease. Identification of biomarkers for early diagnosis and prediction of disease progression is important. The present comparative proteomic study of serum samples using two-dimensional fluorescence differential gel electrophoresis followed by ELISA confirmation demonstrated that protein expression of Rab35 was increased in PD patients compared with matched control subjects and other parkinsonian disorders, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). The serum level of Rab35 was significantly correlated with the age at onset of PD. The median age of onset in patients with higher Rab35 serum level was 5 years younger than those with lower Rab35 serum level. There was a positive correlation between the Rab35 level and disease duration of PD. Moreover, the protein expression of Rab35 was increased in the substantia nigra but not in the striatum of mouse models of PD, including MPTP-treated mice, rotenone-treated mice, (R1441C) LRRK2 or (G2019S) LRRK2 transgenic mice. Furthermore, overexpression of Rab35 increased the aggregation and secretion of mutant A53T α-synuclein in dopaminergic SH-SY5Y cells. Co-expression of Rab35 with wild-type or A53T α-synuclein in SH-SY5Y cells deteriorated cell death. Our results suggest that Rab35 is potentially useful in the differential diagnosis of parkinsonian disorders and is implicated in the pathogenesis of PD.

In vivo detection of monoaminergic degeneration in early Parkinson disease by (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET.

UNLABELLED: PET with (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine ((18)F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. METHODS: The aim of this study was to evaluate the capability of (18)F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent (18)F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized volumes of interest were applied to the spatial normalized image for quantification analysis. The specific uptake ratios (SURs) were calculated according to the formula (specific volumes-of-interest counts/occipital cortex counts) - 1. SUR measurements were summarized for each brain region. RESULTS: The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5-5 y). The mean mHY was 1.0 ± 0.1 (range, 1-1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The reduction of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (-81%), followed by the ipsilateral posterior putamen (-67%). Receiver-operating-characteristic curve analysis showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. CONCLUSION: (18)F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of (18)F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that (18)F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.

Correlation of Parkinson disease severity and 18F-DTBZ positron emission tomography.

IMPORTANCE: Currently, diagnosis of Parkinson disease is mainly based on clinical criteria characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Reliable in vivo biomarkers to monitor disease severity and reflect the underlying dopaminergic degeneration are important for future disease-modifying therapy in Parkinson disease. OBJECTIVES: To use [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-DTBZ; [18F]AV-133) positron emission tomography (PET) to explore the characteristics of vesicular monoamine transporter type 2 imaging in patients with Parkinson disease (PD) with different severity levels as well as to investigate its capability in monitoring clinical severity. DESIGN, SETTING, AND PARTICIPANTS: Regional uptakes for 18F-DTBZ PET of different disease stages were measured. Seventeen healthy control participants and 53 patients in 3 groups of mild, moderate, and advanced stages of PD were recruited for 18F-DTBZ PET scans from the Movement Disorders Clinic in the Chang Gung Memorial Hospital, Taiwan. MAIN OUTCOMES AND MEASURES: The severity of disease in patients with PD was quantified by modified Hoehn-Yahr Scale, Unified Parkinson Disease Rating Scale total scores and subscores of posture instability and gait disturbance, tremor, akinesia, and rigidity while not taking medication. Both voxelwise- and volume of interest-based image analyses were performed. The specific uptake ratio (SUR) of each volume of interest and voxel was calculated as (target uptake - reference uptake) / reference uptake using the occipital reference region from magnetic resonance imaging-based spatially normalized 18F-DTBZ images for each participant. Average SUR images were displayed as 2-dimensional and 3-dimensional to illustrate the image patterns in each group. The nonparametric Kruskal-Wallis test on regional SUR was used for group comparison between healthy control participants and patients with PD at different stages. Quantitative parameters were correlated with severity of disease and disease duration by Spearman correlation. Voxelwise analysis for evaluating dopaminergic neuron decline of different PD stages was performed by SPM5. RESULTS: The 2-dimensional and 3-dimensional 18F-DTBZ PET images demonstrated that the reduction of vesicular monoamine transporter type 2 availability was obviously correlated with the severity of disease in patients with PD. The mean reductions of vesicular monoamine transporter type 2 density for the caudate, putamen,and substantia nigra were 21.50%, 58.20%, and 21.10% for mild PD[Parkinson disease];60.75%, 79.49%,and 39.87%formoderate PD; and63.94%,83.20%, and 44.00% for advanced PD, respectively [corrected]. The SURs of bilateral striatal regions exhibited significantly exponential correlations to stage; disease duration; Unified Parkinson Disease Rating Scale motor score; posture instability and gait disturbance; and akinesia, rigidity, and tremor scores. CONCLUSIONS AND RELEVANCE: In PD, 18F-DTBZ PET is a potential imaging biomarker for measuring dopaminergic degeneration in vivo and monitoring the severity of disease.