Faculty Bibliography

Objective: The objective of this report was to perform secondary subset analysis in the MASTER-PD study exploring which specific motor symptom within UPDRS III improved with high frequency rTMS over motor cortex (M1) among Parkinson's disease (PD) patients. Background: TMS has shown to improve motor symptoms in PD particularly high frequency stimulation over the M11. The primary results of the MASTER-PD study confirmed that bilateral M1 stimulation is better than sham for motor symptoms in PD. However, there are only a few reports that mention which specific motor symptoms improve. Methods: 29 PD subjects were included in this subset analysis of the MASTER-PD study which was a multicenter, double-blind, sham-controlled, parallel-group trial. TMS protocol consisted of daily sessions of 2000 stimuli (50 x 4-sec trains of 40 stimuli at 10Hz) for 10 days, Monday to Friday for two consecutive weeks over bilateral M1 vs. placebo. Patients were evaluated OFF PD medications at baseline and 1 month post treatment. Sub-scores were calculated using aggregates of different items in UPDRS III. Outcome subscores were bradykinesia, rigidity, axial symptoms and tremor. Results: Baseline demographic and clinical variables were comparable between the 2 groups. Total UPDRS III score decreased more in the M1 group than the sham group (-4.9 points vs. -0.3 points; t=-2.1, p<0.05,). Post-hoc analysis revealed that only bradykinesia (-0.29 points vs. -0.01 points; t=-2.099, p=0.045) and rigidity (-0.2 points vs. 0.24 points; t=-2.955, p=0.006) decreased more in the M1 group than sham group. Conclusion: The results of our study demonstrate that high frequency rTMS over bilateral M1in PD is effective for improving bradykinesia and rigidity. This may reflect the potential for developing targeted rehabilitation for specific motor symptoms based on rTMS frequency and specific cortical regions

BACKGROUND: In Parkinson's disease (PD), skill retention is poor, even when acquisition rate is generally preserved. Recent work in normal subjects suggests that 5 Hz-repetitive transcranial magnetic stimulation (5Hz-rTMS) may induce phenomena of long-term potentiation at the cortical level. OBJECTIVE/HYPOTHESIS: We thus verified whether, in PD, 5Hz-rTMS enhances retention of a visuo-motor skill that involves the activity of the right posterior parietal cortex. METHODS: A group of patients with PD was tested in two two-day sessions, separated by one week (treatment and placebo sessions). The first day of each session, they learned to adapt their movements to a step-wise 60 degrees visual rotation. Immediately after the task, either real 5Hz-rTMS (treatment) or sham (placebo) stimulation was applied over the right posterior parietal cortex (P6). Retention of this motor skill was tested the following day. RESULTS: In patients with PD, adaptation achieved at the end of training was comparable in the treatment and placebo sessions and was similar to that of a group of age-matched controls. However, retention indices tested on the following day were significantly lower in the placebo compared to the treatment session in which retention indices were restored to the level of the controls. Importantly, reaction and movement time as well as other kinematic measures were the same in the treatment and placebo sessions. CONCLUSION: These results suggest that rTMS applied after the acquisition of a motor skill over specific areas involved in this process might enhance skill retention in PD.

OBJECTIVE: In untreated Fabry patients without overt autonomic dysfunction and normal baroreflex sensitivity (BRS) at rest, BRS is impaired during orthostatic, sympathetic challenge but normalizes after enzyme-replacement therapy (ERT) (Hilz et al., J Hypertens 2010; 28:1438-1448). This study evaluated BRS during parasympathetic challenge with six cycles per minute metronomic deep breathing (MDB) in Fabry patients before and after ERT. METHODS: In 22 Fabry patients (28 +/- 8years), we monitored RR-intervals (RRIs), SBP, and respiratory frequency during spontaneous breathing (spont_breath) and MDB, before and after 18 (11 patients) or 23 months (11 patients) of biweekly ERT (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) RRI fluctuations, parasympathetic high-frequency (0.15-0.5 Hz) RRI fluctuations, sympathetically mediated low-frequency powers of SBP and high-frequency powers of SBP. We calculated BRS (ms/mmHg) during spont_breath and MDB as low-frequency-high-frequency alpha index (coherence >0.5). We compared parameters during spont_breath and MDB within and between patients before and after ERT and 15 age-matched (27 +/- 5years) healthy men (RANOVA and posthoc analysis; significance: P < 0.05). RESULTS: During spont_breath and MDB, parameters were similar between groups. Within the three groups, RRIs were lower, whereas RRI low-frequency powers and SBP low-frequency powers were higher during MDB than during spont_breath. BRS was similar during MBD and spont_breath in untreated patients (P > 0.05), but increased significantly with MDB in patients after ERT (P = 0.048) and in controls (P = 0.035). CONCLUSION: In untreated Fabry patients, MDB uncovers impaired BRS. After 18 or 23 months of ERT, MDB-induced BRS increase is similar in Fabry patients and controls, demonstrating that ERT not only restores sympathetic but also parasympathetic baroreflex activation

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL=18, 69.9+/-6.7 years) and subjects with mild cognitive impairment (MCI=15, 74.9+/-8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL=17, MCI=7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (rho=-0.41, P=0.049) and global cortical (rho=-0.46, P=0.02) vasoreactivity to hypercapnia (VR(h)). The FCRP-VR(h) relationships were most pronounced in the MCI group: hippocampus (rho=-0.77, P=0.04); global cortex (rho=-0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR(h) was lower in MCI than in NL subjects (Z=-2.0, P=0.047). This difference persisted after age and FCRP correction (F([3,20])=4.6, P=0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR(h) is more sensitive to vascular burden than either resting CBF or brain volume

Due to methodological difficulties related to the small size, variable distribution of hippocampal arteries, and the location of the hippocampus in the proximity of middle cranial fossa, little is known about hippocampal blood flow (HBF). We have tested the utility of a pulsed arterial spin labeling sequence based on multi-shot true fast imaging in steady precession to measure HBF in 34 normal volunteers (17 women, 17 men, 26-92 years old). Flow sensitivity to a mild hypercapnic challenge was also examined. Coregistered 3D MPRAGE sequence was used to eliminate from hippocampal and cortical regions of interest all voxel with <75% of gray matter. Large blood vessels were also excluded. HBF in normal volunteers averaged 61.2 +/- 9.0 mL/(100 g min). There was no statistically significant age or gender effect. Under a mild hypercapnia challenge (end tidal CO(2) pressure increase of 6.8 +/- 1.9 mmHg over the baseline), HBF response was 14.1 +/- 10.8 mL/(100 g min), whereas cortical gray matter flow increased by 18.0 +/- 12.2 mL/(100 g min). Flow response among women was significantly larger than in the men. The average absolute difference between two successive HBF measures was 3.6 mL/(100 g min) or 5.4%. The 3T true fast imaging in steady precession arterial spin labeling method offers a HBF measurement strategy that combines good spatial resolution, sensitivity, and minimal image distortions. Magn Reson Med, 2010. (c) 2010 Wiley-Liss, Inc

OBJECTIVE: Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT). METHODS: In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05). RESULTS: Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05). CONCLUSION: Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis

BACKGROUND AND PURPOSE: It is not clear how cardiovascular autonomic nervous system dysfunction can affect falls in Parkinson disease (PD) patients. The aim of the study was to evaluate cardiovascular autonomic responses to orthostatic stress and occurrence of falls in PD patients over a period of 1-2 years. MATERIAL AND METHODS: In 53 patients, who either experienced at least one fall during 12 months preceding the study onset (fallers) or did not fall (non-fallers), we monitored RR intervals (RRI), heart rate (HR) and systolic (SBP) and diastolic (DBP) blood pressure, and calculated the coefficient of variation of RRI (RRI-CoV) and the ratio of low to high frequency spectral powers of RRI oscillations (LF/HF) at rest and upon tilting at study entry and after at least 12 months. Based on the number of falls at study closure, we identified three subgroups: non-fallers, chronic fallers, and new fallers. RESULTS: At study entry, RR-CoV, SBP, or DBP did not differ between fallers and non-fallers, while LF/HF ratios were lower in fallers than non-fallers at rest and upon tilting. After the follow-up period, HR and RRI-CoV responses to head-up tilt were reduced in new fallers as compared to study entry, whereas these variables remained unchanged during the study in non-fallers and chronic fallers. Prevalence of orthostatic hypotension did not differ between subgroups of patients. CONCLUSIONS: Cardiac responses to orthostatic stress deteriorate in PD patients who begin to fall. Orthostatic blood pressure responses remain unchanged over time and are not associated with falls in PD.