Masayuki Yoshioka

Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease

BACKGROUND In our previous study, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and the vitamin D receptor (VDR) FokI CC genotype were associated with milder Parkinson disease (PD). OBJECTIVE We evaluated whether vitamin D3 supplementation inhibits the progression of PD on the basis of patient VDR subgroups. DESIGN Patients with PD (n = 114) were randomly assigned to receive vitamin D3 supplements (n = 56; 1200 IU/d) or a placebo (n = 58) for 12 mo in a double-blind setting. Outcomes were clinical changes from baseline and the percentage of patients who showed no worsening of the modified Hoehn and Yahr (HY) stage and Unified Parkinsons Disease Rating Scale (UPDRS). RESULTS Compared with the placebo, vitamin D3 significantly prevented the deterioration of the HY stage in patients [difference between groups: P = 0.005; mean ± SD change within vitamin D3 group: +0.02 ± 0.62 (P = 0.79); change within placebo group: +0.33 ± 0.70 (P = 0.0006)]. Interaction analyses showed that VDR FokI genotypes modified the effect of vitamin D3 on changes in the HY stage (P-interaction = 0.045), UPDRS total (P-interaction = 0.039), and UPDRS part II (P-interaction = 0.021). Compared with the placebo, vitamin D3 significantly prevented deterioration of the HY stage in patients with FokI TT [difference between groups: P = 0.009; change within vitamin D3 group: -0.38 ± 0.48 (P = 0.91); change within placebo group, +0.63 ± 0.77 (P = 0.009)] and FokI CT [difference between groups: P = 0.020; change within vitamin D3 group: ±0.00 ± 0.60 (P = 0.78); change within placebo group: +0.37 ± 0.74 (P = 0.014)] but not FokI CC. Similar trends were observed in UPDRS total and part II. CONCLUSION Vitamin D3 supplementation may stabilize PD for a short period in patients with FokI TT or CT genotypes without triggering hypercalcemia, although this effect may be nonspecific for PD. This trial was registered at UMIN Clinical Trials Registry as UMIN000001841.

Cardiovascular dysautonomia in de novo Parkinson's disease

BACKGROUND Clinical symptoms of Parkinsons disease (PD) include not only motor distress, but also autonomic dysfunction. OBJECTIVE To clarify the progression of autonomic nervous dysfunction in PD. METHODS The subjects were 44 patients with de novo PD. Autonomic nervous function, including cardiac sympathetic gain, was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure. RESULTS Decreased cardiac MIBG uptake was found even in patients with early stage PD. MIBG uptake gradually decreased with increased disease severity. Hemodynamic studies using the Valsalva maneuver revealed that patients with early stage PD had reduced baroreceptor reflex sensitivity (BRS) in phase II, but not phase IV. Blood pressures normally rose in phases II and IV, but the increments decreased with disease progression. In early stage PD, the low frequency power of the RR interval (RR-LF) and the ratio (LF/HF) of RR-LF to the high frequency component of the RR interval (RR-HF) were significantly lower than the respective control values, despite no significant difference in RR-HF; these variables decreased with disease progression. CONCLUSION Our results show that latent sympathetic nervous dysfunction without parasympathetic dysfunction, especially that involving the sinus node, is already present in early stage de novo PD. It is unclear whether the responsible lesion is central or peripheral.

Cardiovascular autonomic dysfunction in dementia with Lewy bodies and Parkinson's disease

OBJECTIVE We estimated the extent and pattern of cardiovascular autonomic dysfunction in dementia with Lewy bodies (DLB) as compared with that in Parkinsons disease (PD). METHODS We performed meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy of the heart and hemodynamic autonomic function testing using the Valsalva maneuver in 27 patients with DLB, 46 with PD, and 20 controls. RESULTS (123)I-MIBG uptakes in DLB were reduced as compared with those in control and PD. Hemodynamic studies revealed that DLB had decreased baroreceptor reflex and reduced responses of SBP in phases II and IV as compared with PD and control. SBP responses on standing and the difference in plasma norepinephrine (NE) concentrations between supine and standing positions were reduced in PD as compared with those in control. Furthermore, SBP responses on standing, plasma NE concentrations in supine and standing positions, and the difference in plasma NE concentrations between these positions were significantly lower in DLB than in PD and control. Plasma NE concentrations in DLB with orthostatic hypotension (OH) were lower than that in DLB without OH, although some patients who had DLB with orthostatic hypotension had relatively normal plasma NE levels. CONCLUSION Cardiovascular autonomic dysfunction is more severe in DLB than in PD and is usually caused by the loss of postganglionic sympathetic nervous function, although dysautonomia in some patients with DLB may result from preganglionic dysfunction.

25-hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson's disease.

We aimed to examine associations among serum 25‐hydroxyvitamin D levels, 1,25‐dihyroxyvitamin D levels, vitamin D receptor polymorphisms, vitamin D binding protein gene polymorphisms, and the severity of Parkinsons disease. In 137 patients, the severity of Parkinsons disease was evaluated using Hoehn & Yahr stage and Unified Parkinsons Disease Rating Stage by neurologists and compared with 25‐hydroxyvitamin D, 1,25‐hydroxyvitamin D, vitamin D receptor polymorphisms, ie, FokI (rs10735810), BsmI (rs1544410), Cdx2 (rs11568820), ApaI (rs7976091), and TaqI (rs731236), and vitamin D binding protein gene polymorphisms GC1 (rs7041)/GC2 (rs4588) in a cross‐sectional study. Mean ± standard deviation levels of 25‐hydroxyvitamin D were 21.1 ± 9.0 ng/mL. Levels were deficient (<20 ng/mL) in 49% of patients. In contrast, 1,25‐hydroxyvitamin D levels were considered normal in all patients. Higher circulating 25‐hydroxyvitamin D levels were significantly associated with milder Parkinsons disease evaluated by Hoehn & Yahr stage (P = .002) and total Unified Parkinsons Disease Rating Stage (P = .004) even after multivariate adjustment for 8 covariates, including disease duration. However, significant associations were not observed in 1,25‐hydroxyvitamin D levels. Under multivariate analysis with 25‐hydroxyvitamin D as well as other 8 covariates including disease duration, carriers of vitamin D receptor FokICC genotype had a milder form of Parkinsons disease: odds ratio, 0.32; 95% confidence interval, 0.16 to 0.66, P = 0.002. These results suggest that higher 25‐hydroxyvitamin D levels and the vitamin D receptor FokICC genotype may be independently associated with milder forms of Parkinsons disease. However, significant associations were not observed in 1,25‐hydroxyvitamin D levels.

Evaluation of Baroreflex Sensitivity by the Sequence Method Using Blood Pressure Oscillations and R–R Interval Changes during Deep Respiration

Background: Baroreflex sensitivity assessments have been considered to be important to evaluate cardiac autonomic neuropathy. The phenylephrine method, Valsalva maneuver or sequence method at rest caused several problems. We evaluated the usefulness of the sequence method during deep respiration. Method: Baroreflex sensitivity was evaluated in 20 normal volunteers and 50 patients with Parkinson’s disease. R–R intervals and systolic blood pressures were obtained by electrocardiogram and tonometry using a continuous blood pressure monitoring system. The sequence method is an evaluation of baroreflex sensitivity using sequences of 3 or more consecutive beats for 4 min. Baroreflex sensitivity was also assessed by the Valsalva maneuver at 5 beats before the peak systolic blood pressure of phase IV. The slope of the linear interrelationship between systolic blood pressure and the following R–R interval, i.e. baroreflex sensitivity (ms/mm Hg), was calculated with a correlation coefficient greater than 0.8. Result: The mean value of baroreflex sensitivity obtained by the Valsalva maneuver was 7.91 in normal volunteers and 5.35 in patients with Parkinson’s disease; the one obtained by the sequence method at rest was 9.10 in normal volunteers and 8.42 in patients with Parkinson’s disease, and the one obtained by the sequence method during deep respiration was 10.23 in normal volunteers and 6.73 in patients with Parkinson’s disease. In some cases with Parkinson’s disease, baroreflex sensitivities could not be found, whereas in all patients with Parkinson’s disease, the sequence method during deep respiration could be used for evaluations. Significant correlations were found among the baroreflex sensitivities obtained by the Valsalva maneuver, and the sequence method at rest or during deep respiration in normal volunteers and patients with Parkinson’s disease. Conclusions: The baroreflex sensitivity obtained by the sequence method during deep respiration could be investigated noninvasively in all cases with PD, being thus a useful method for clinical evaluation of baroreflex sensitivity.

The odor stick identification test for Japanese differentiates Parkinson's disease from multiple system atrophy and progressive supra nuclear palsy

BackgroundProgressive supranuclear palsy (PSP) and parkinsonian variant of multiple system atrophy (MSA-P) are clinically difficult to differentiate from idiopathic Parkinsons disease (PD), particularly in the early stages of the disease. Previous reports indicated that the olfactory function is relatively intact or slightly reduced in patients with PSP and MSA-P, suggesting that the odor stick identification test for Japanese (OSIT-J), which is a short and simple noninvasive test that is potentially useful clinically for detecting early-stage PD in Japan, may be useful in the differential diagnosis of early-stage PD from MSA-P and PSP. There is no information on the sensitivity and specificity of OSIT-J in the diagnosis of parkinsonian syndromes such as PSP and MSA-P.MethodsWe assessed the olfactory function using the OSIT-J test in 94 Japanese patients with idiopathic PD, 15 with MSA-P, 7 with PSP, and 29 age-matched control subjects.ResultsThe mean ± SD score of OSIT-J in patients with PD (4.4 ± 2.9) was significantly lower than in patients with MSA-P (8.7 ± 2.2, P < 0.0001), PSP (7.6 ± 2.2, P < 0.0057), and control subjects (10.5 ± 1.3, P < 0.0001). The area under the curve (AUC) of receiver operating characteristic (ROC) to discriminate PD from normal control using OSIT-J scores was 0.97 (95% confidence interval, 0.95-1.00), from MSA-P 0.87 (0.80-0.95), and from PSP 0.81 (0.66-0.96).ConclusionThe OSIT-J is a potentially useful clinical test not only for detection of olfactory deficit in PD but also for differentiating PD from MSA-P and PSP.

Impaired cardiovascular autonomic function in Parkinson's disease with visual hallucinations.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinsons disease (PD). The subjects were 37 patients without VH (VH(−)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123‐radioiodinated metaiodobenzylguanidine (123I‐MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt‐table testing. 123I‐MIBG uptake was lower in VH(+) than VH(−). Hemodynamic studies showed that VH(−) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt‐table testing was greater in VH(+) than VH(−). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(−). Severe dysfunction in PD with VH is probably attributed to Lewy‐body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both.

Cardiovascular dysautonomia in Parkinson's disease and multiple system atrophy

Objectives - To determine whether Parkinsons disease (PD) can be distinguished from multiple system atrophy (MSA) on the basis of the assessment of iodine-123 meta-iodobenzylguanidine ( 123 I-MIBG) radioactivity in heart and cardiovascular autonomic function. Patients and methods - Seventeen patients with MSA, 39 with PD, and 25 healthy volunteers underwent 123 I-MIBG scintigraphy and hemodynamic autonomic function tests using Valsalva maneuver (VM). Baroreceptor reflex sensitivity (BRS) was measured using the slope of the relation between RR interval and blood pressure during the fourth phase. Results - 123 I-MIBG radioactivity in heart of patients with PD was lower than that of control subjects and patients with MSA, but there was some overlap between PD and MSA. BRS in patients with PD who had a 123 I-MIBG radioactivity similar to that in MSA was larger than that in patients with MSA, with no overlap in any patient. Conclusion - Assessment of BRS may be useful for differentiating between MSA and PD that had a 123 I-MIBG radioactivity similar to MSA.

Postnatal development of GABAergic axon terminals in the rat nucleus of tractus solitarius

The proper function of the brain depends on a precise arrangement of excitatory and inhibitory synapses. Although the caudal nucleus of tractus solitarius (cNTS) plays a pivotal role in cardiorespiratory reflexes, we know little about the formation of the local neural network in the cNTS. In the present study, we have focused on GABAergic axon terminals and investigated postnatal changes in GABAergic synaptic organizations in the rat cNTS immunocytochemically at both light and electron microscopic levels. Counting synaptic and non-synaptic GABAergic axon terminals revealed that GABAergic axon terminal number in the cNTS seemed constant until the second postnatal week and that GABAergic axon terminals were reorganized around postnatal day 10 (P10). Electron microscopic observation revealed that more than 20% GABAergic axon terminals formed axosomatic synapses at P2 to P4, but the number of GABAergic axosomatic synapse on neurons with smaller soma (smaller neurons) decreased considerably after P8. Orphan GABAergic boutons were present around somata of smaller neurons at P10, and axodendritic synapse number on thicker dendrites decreased gradually during postnatal development. These results show that GABAergic axon terminals detach from somata of smaller neurons at the second postnatal week. Such morphologic changes in axon terminals could cause changes in electrophysiological activity and might contribute to reorganization of the local network within the cNTS from neonatal to adult type. These postnatal changes in the cNTS local network might be prerequisite for the cardiorespiratory reflexes of the adult type.

Cardiovascular dysautonomia in Parkinson's disease and multiple system atrophy [This article has been retracted]

Objectives –  To determine whether Parkinsons disease (PD) can be distinguished from multiple system atrophy (MSA) on the basis of the assessment of iodine‐123 meta‐iodobenzylguanidine (123I‐MIBG) radioactivity in heart and cardiovascular autonomic function.