Rasagiline does not exacerbate autonomic blood pressure dysregulation in early or mild Parkinson's disease.

INTRODUCTION: Orthostatic hypotension (OH) and abnormal blood pressure (BP) fluctuations occur mainly due to noradrenergic dysfunction and are clinically important in patients with Parkinson's disease (PD). They lead to impairments of cognition function, daily activities, and quality of life. Some monoamine oxidase (MAO)-B inhibitors have a sympathomimetic amine, which can be attributed to OH. Therefore, we determined whether rasagiline, a common MAO-B inhibitor used in PD treatment, can contribute to cardiovascular autonomic BP dysregulation in patients with early or mild PD. METHODS: Nineteen patients with early or mild PD were recruited, and tilt test and 24-h ambulatory BP monitoring (ABPM) were performed before and after rasagiline administration. Early or mild PD was defined as patients with de novo (n = 4), levodopa (n = 10), dopamine agonist (n = 1), levodopa and one dopamine agonist (n = 2), levodopa and droxidopa (n = 1), and levodopa and istradefylline (n = 1). Furthermore, patients with motor fluctuation and multiple dopamine agonists were excluded from our study. RESULTS: OH and BP frequency were not significantly exacerbated before or after rasagiline administration. No significant differences of type in BP fluctuation on ABPM and the degree of nocturnal BP falls were found before and after rasagiline administration. The Unified Parkinson's Disease Rating Scale motor score in patients (post-rasagiline administration) was significantly improved compared with before. CONCLUSION: Rasagiline seems to be a suitable medication for Parkinsonian symptoms in patients with early and mild PD. It does not exacerbate cardiovascular autonomic responses, circadian rhythm of BP, or both.

Frontal lobe dysfunction is associated with reduced DAT-SPECT accumulation in Lewy body disease.

INTRODUCTION: Lewy body disease (LBD) causes olfactory or cognitive dysfunction even before motor symptoms emerge. Recent reports indicate that the dopamine transporter (DAT), which can be imaged using single-photon emission computed tomography (123I-ioflupane SPECT), is related to olfactory and cognitive dysfunction in LBD patients. We suspected that decreased cerebral blood flow (CBF) in the frontal lobe might be involved in these relationships. If so, then the results of these examinations may be useful in assessing the pathological progression of Lewy bodies. METHODS: We retrospectively analyzed the data of 139 de novo consecutive patients with LBD. We used the Odor Stick Identification Test for Japanese (OSIT-J) and the Frontal Assessment Battery (FAB) to evaluate olfactory and frontal lobe dysfunction, respectively. Among the 139 patients, ultimately 84 patients were analyzed and underwent 123I-ioflupane SPECT within 3 months (before or after) of the OSIT-J and FAB. We categorized patients on the basis of whether frontal lobe CBF was reduced (n = 28) or normal (n = 56). RESULTS: The average OSIT-J and FAB scores were 4.0 and 14.1, respectively, and the scores on the two tests were significantly correlated. Furthermore, OSIT-J scores were significantly correlated with the specific binding ratio (SBR) in both groups. The SBR was correlated with FAB scores in patients with reduced CBF in the frontal lobe, but not in those with normal CBF. CONCLUSION: Frontal lobe dysfunction and striatum dysfunction are correlated in LBD patients only after CBF has declined. Also, there is a time lag in the appearance of olfactory dysfunction and frontal lobe dysfunction in LBD patients. As with pathological development, olfaction is impaired earliest, followed by striatal, and then frontal lobe dysfunction.

Association between heart rate variability and striatal dopamine depletion in Parkinson's disease.

Striatal dopamine depletion is associated with not only motor symptom but also non-motor symptoms in patients with Parkinson's disease (PD). The purpose is to elucidate the relation between heart rate variability (HRV) and dopaminergic depletion in specific striatal subregions. The subjects were 84 patients with newly diagnosed untreated PD. All patients underwent striatal 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single-photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. Association of HRV with dopaminergic depletion in specific striatal subregions was examined. HRV was related to dopamine depletion in the caudate and anterior putamen, especially the left side, after controlling for age, hemoglobin A1c level, disease duration, motor severity and global cognition on multiple regression analysis (left caudate p = 0.012). HRV was closely related to striatal dopamine depletion, especially in the left associative striatum, in patients with PD.

Clinical and neuroendocrinological characteristics of delayed orthostatic hypotension in Parkinson's disease.

PURPOSE: Delayed orthostatic hypotension (DOH), a fall in blood pressure after a 3-min cutoff, is clinically meaningful. The aim of this study was to elucidate the clinical and neuroendocrinological characteristics of DOH in patients with Parkinson's disease (PD). METHODS: A total of 132 patients with newly diagnosed PD were enrolled. Baseline clinical characteristics, including olfactory function, and changes in norepinephrine (NE) and vasopressin (ADH) concentrations during the head-up tilt test (HUT), were examined. RESULTS: Fifty-five patients (42%) had classical orthostatic hypotension (COH), and 19 patients (14%) had DOH. Patients with COH and DOH tended to have more severe hyposmia than patients without OH. A multivariate linear regression model showed that hyposmia was associated with DOH and COH. The increase of heart rate against the fall in blood pressure was significantly lower in patients with COH and DOH than those without OH. The NE levels at supine rest and after upright tilting were lower in the COH group than in the PD without OH and DOH groups. The levels of ADH were higher in the DOH group than in the COH group at supine rest and higher than in the PD without OH group after upright tilting. There was no significant difference in the cardiac 123I-MIBG scintigraphy between the COH and DOH groups. CONCLUSION: Compared with patients without OH, patients with DOH had severe hyposmia. Relatively preserved peripheral sympathetic nervous system function in patients with DOH suggests that DOH might be an early and milder form of OH in PD.

Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson's Disease.

BACKGROUND: Orthostatic hypotension (OH) at an early stage of Parkinson's disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH. OBJECTIVE: We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD. METHODS: Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. The association between hemodynamic changes and 123I-FP-CIT uptake was examined. RESULTS: 123I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with 123I-FP-CIT uptake in bilateral anterior putamen (left: p < 0.01, right: p < 0.05) and left posterior putamen (p < 0.05). Patients with OH had more severe dopamine depletion in left anterior (p = 0.008) and posterior (p = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p = 0.024). CONCLUSION: OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH.

Comparisons of cardiovascular dysautonomia and cognitive impairment between de novo Parkinson's disease and de novo dementia with Lewy bodies.

BACKGROUND: Cognitive impairment may be correlated with cardiovascular dysautonomia, including blood pressure (BP) dysregulation, in Parkinson's disease (PD), but the association between these factors in dementia with Lewy bodies (DLB) is uncertain. This study aimed to clarify whether cardiovascular dysautonomia had an influence on cognitive function in Lewy body disease or not. METHODS: Ninty-nine patients with de novo PD (n = 75) and DLB (n = 24) were evaluated using the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension (PPH), nocturnal BP fall in 24-h ambulatory blood pressure monitoring (ABPM) and constipation were estimated. Associations of these factors with cognitive and executive dysfunction were examined. RESULTS: In DLB, MIBG uptake was reduced and OH, PPH and SH were severely disturbed, compared to PD. The nocturnal BP fall in ABPM was lower in DLB, and the failure of nocturnal BP fall in PD was associated with MMSE, after adjustment for other clinical features. FAB was significantly associated nocturnal BP fall, age and SH in PD, but no significant correlations among factors were found for DLB. CONCLUSION: The significant association between nocturnal BP dysregulation and cognitive or executive decline in PD might be due to impaired microvascular circulation or invasion of α-synuclein in the CNS. The lack of a correlation of BP insufficiency with cognitive impairment in DLB suggests initial involvement of Lewy body pathology in the neocortex, regardless of Lewy body invasion of the autonomic nervous system.

Sympathetic nervous activity and hemoglobin levels in de novo Parkinson's disease.

PURPOSE: Sympathetic nervous denervation may be associated with the development of anemia. We aimed to investigate the association between sympathetic nervous denervation and hemoglobin levels in patients with Parkinson's disease (PD). METHODS: As indices of sympathetic nervous denervation, we investigated resting norepinephrine levels, increased norepinephrine levels after tilt-up, cardiac uptake of 123I-metaiodobenzylguanidine, supine blood pressure, and the degree of orthostatic hypotension in 132 patients with de novo PD. RESULTS: Older age, female sex, severe motor dysfunction, and lower body mass index were associated with decreased hemoglobin levels. After adjustment for these covariables, resting norepinephrine levels were negatively associated with hemoglobin levels. Hemoglobin levels were not associated with cardiac sympathetic denervation or orthostatic intolerance. CONCLUSION: Hemoglobin levels in PD seem to be closely related to noradrenergic nervous activity and nigrostriatal dopaminergic degeneration. In contrast to expectations, decreased hemoglobin levels were associated with increased whole-body sympathetic nervous activity in PD.

Differential leukocyte count is associated with clinical phenotype in Parkinson's disease.

INTRODUCTION: Elevated proinflammatory cytokines are associated with disease progression in patients with Parkinson's disease (PD). The aim of study is to investigate whether components of peripheral blood leukocyte are associated with clinical symptoms in patients with de novo PD. METHODS: We analyzed data from 123 newly diagnosed de novo patients who had no focal and systemic inflammatory diseases. Associations between clinical symptoms and differential leukocyte count (DLC) or DLC associated peripheral inflammatory biomarkers were examined. RESULTS: Altered DLC and DLC associated peripheral inflammatory biomarkers were associated with PD related symptoms even though there was no sign of clinical inflammation. After controlling for covariables, olfaction and body mass index (BMI) were inversely associated with percentage of neutrophil, neutrophil to lymphocyte ratio, derived neutrophil to lymphocyte ratio, and positively associated with percentage of lymphocyte, lymphocyte to monocyte ratio. Patients with tremor-dominant or mixed type had lower peripheral inflammatory indices than those with akinetic rigid type. CONCLUSION: Components of peripheral blood leukocytes reflect some clinical symptoms of PD. Patients with normosmia, tremor-dominant or mixed type, and patients without low BMI have low peripheral inflammatory indices. Relative mild peripheral inflammation may play one of major roles in developing mild disease phenotype in these patients.

High norepinephrinergic orthostatic hypotension in early Parkinson's disease.

INTRODUCTION: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. METHODS: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH+low NEsupine. RESULTS: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (<251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (p = 0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. CONCLUSIONS: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.

Predictors of postprandial hypotension in elderly patients with de novo Parkinson's disease.

Postprandial hypotension is one of the most important autonomic disorders in Parkinson's disease. However, its predictors remain unclear. We investigated which variable(s) predict the presence of postprandial hypotension in elderly patients with Parkinson's disease. The subjects were 64 patients with de novo Parkinson's disease who were 70 years or older. Postprandial hypotension was evaluated on a 75-g oral glucose tolerance test. Olfactory function, constipation, cardiac sympathetic or parasympathetic denervation, orthostatic intolerance on head-up tilt table testing, and other baseline characteristics were evaluated. The results showed the presence of postprandial hypotension was associated with severe dysosmia, constipation, orthostatic hypotension (a decrease in systolic blood pressure ≥30 mmHg) and preprandial hypertension at rest. On multiple logistic regression analyses adjusted for age, sex, symptom duration, disease severity, and motor subtype, the odds ratio was 4.02 for severe dysosmia (p = 0.027), 9.99 for constipation (p = 0.006), 6.42 for orthostatic hypotension with alternative definition (p = 0.004) and 7.90 for preprandial hypertension at rest (p = 0.001). Each multiple logistic regression analysis revealed that female sex was also a risk factor for postprandial hypotension. The variables with the highest sensitivity and specificity for postprandial hypotension were constipation (89.6 %) and preprandial hypertension at rest or orthostatic hypotension with alternative definition (both 77.1 %), respectively. Our results suggest that these variables predict the presence of postprandial hypotension in elderly patients with Parkinson's disease, suggesting that postprandial hypotension shares etiologic factors with these potential predictors.