Cardiovascular dysautonomia in de novo Parkinson’s disease without orthostatic hypotension

Background: Clinical symptoms of Parkinson’s disease (PD) include not only motor distress, but also autonomic dysfunction. Objective: To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). Methods: 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 in 20 patients with de novo PD without OH. Results: Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR‐LF to RR‐HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. Conclusion: These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.     

Coping strategies for visual hallucinations in Parkinson's disease.

We assessed the use of coping strategies in Parkinson's disease patients with visual hallucinations, using a semi-structured questionnaire. We found that 36 of our 46 Parkinson's disease subjects with hallucinations (78%) used coping strategies: cognitive techniques in 69%; interactive techniques in 62%; and visual techniques in 33%.     

Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries.

We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac (123)I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.     

Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease?

Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta‐1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 ± 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score ≥ 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R–R intervals, head‐up tilt test, norepinephrine and dobutamine infusion tests, and cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy. The coefficient of variation of R–R intervals and the systolic blood pressure changes accompanying the head‐up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The ¹²³I‐metaiodobenzylguanidine heart‐to‐mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac ¹²³I‐metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease. © 2011 Movement Disorder Society     

MIBG scintigraphy for differentiating Parkinson's disease with autonomic dysfunction from Parkinsonism‐predominant multiple system atrophy

Parkinson's disease (PD) with autonomic dysfunction is difficult to differentiate from Parkinsonism‐predominant multiple system atrophy (MSA‐p). This study aimed to analyze the validity of MIBG scintigraphy for PD with autonomic dysfunction and MSA‐p. Thirty‐nine patients (PD: 27 patients, MSA‐p type: 12) and 12 age‐matched controls were prospectively enrolled and underwent MIBG scintigraphy and autonomic function test (AFT). We separately calculated early and delayed heart‐to‐mediastinal (H/M) ratio and washout rates (WRs). AFT was composed of sympathetic skin reflex and parasympathetic tests based on heart rate variability. Abnormal AFT was observed in 17 (63%) of PD and 10 (83%) of MSA‐p. On comparing PD with abnormal AFT with MSA‐p, either the early or delayed H/M ratio in PD was not different from that in MSA‐p (P > 0.05). Only the WR could differentiate PD with abnormal AFT from MSA‐p (47.07 ± 57.48 vs. 31.39 ± 31.52, respectively) (P = 0.026). According to the results, WR may be more useful than the early and delayed H/M ratio to distinguish MSA‐p from PD with abnormal AFT. Furthermore, the MIBG uptake did not reflect the disease duration or severity. © 2009 Movement Disorder Society     

Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease.

[(123)I]Metaiodobenzylguanidine ([(123)I]MIBG) cardiac scintigraphy could be helpful to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), demonstrating that, in PD with autonomic failure but not in MSA, there is a myocardial postganglionic sympathetic dysfunction. To investigate whether this method is more sensitive than standard autonomic testing to detect early involvement of sympathetic cardiac efferent, we analyse MIBG myocardial uptake in 8 PD patients with normal autonomic testing (nondysautonomia PD group, NDPD) in comparison with 10 PD patients with abnormal autonomic testing (dysautonomia PD group, DPD) and 10 MSA patients. Global MIBG uptake was assessed using the ratio of [(123)I]MIBG uptake in the heart to the upper mediastinum (H/M) on planar scintigraphic data. Regional MIBG uptake was determined on two single photon emission tomography scans in regions of the left ventricle. The mean H/M ratios were significantly different among the three groups (P < 0.0001). H/M ratios of both NDPD and DPD patients groups (H/M = 1.83 +/- 0.50 and 1.24 +/- 0.40, respectively) were significantly lower than in MSA patients (H/M = 2.52 +/- 0.60). However, in NDPD patients, H/M was significantly higher than in DPD patients. When compared to MSA patients, NDPD patients showed a regional reduction in MIBG uptake in all left ventricle regions markedly in the apex and the inferior wall. Our results suggest that MIBG myocardial scintigraphy (analysis of both H/M ratio and regional MIBG uptake) may be more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction in PD.     

Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT.

We developed a questionnaire to assess autonomic symptoms in patients with Parkinson's disease (PD) and evaluated its reliability and validity. Based on the results of a postal survey in 46 PD patients, 21 multiple system atrophy patients, and 8 movement disorders specialists, items were included according to their frequency, burden, and clinical relevance. The questionnaire was evaluated in 140 PD patients and 100 controls, and test-retest reliability was established in a sample of 55 PD patients. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction. Test-retest reliability was good. Autonomic problems increased significantly with increasing disease severity for all autonomic regions, except sexual dysfunction. We conclude that SCOPA-AUT is a reliable and valid questionnaire that evaluates autonomic dysfunction in PD.     

Neuropsychological deficits in Parkinson's disease patients with visual hallucinations.

Recent neuropathological and neuroimaging studies suggest the involvement of several temporal regions in Parkinson's disease (PD) patients with visual hallucinations (VH). We examined 24 nondemented PD patients with VH, 21 PD patients without VH, and 21 healthy controls using a battery of tests assessing different aspects of temporal lobe function. PD patients with VH showed poorer performance in language, verbal learning, semantic fluency, and visuoperceptive functions compared to controls and PD patients without VH. Differences in verbal learning and visuoperceptive functions were independent of general cognitive status, disease severity, and depression. We suggest that a wide range of neuropsychological deficits can contribute to the emergence of VH in PD.     

Retinal nerve fiber layer thickness and visual hallucinations in Parkinson's Disease

Defective visual information processing from both central and peripheral pathways is one of the suggested mechanisms of visual hallucination in Parkinson's disease (PD). To investigate the role of retinal thinning for visual hallucination in PD, we conducted a case‐control study using spectral domain optical coherence tomography. We examined a representative sample of 61 patients with PD and 30 healthy controls who had no history of ophthalmic diseases. General ophthalmologic examinations and optical coherence tomography scans were performed in each participant. Total macular thickness and the thickness of each retinal layer on horizontal scans through the fovea were compared between the groups. In a comparison between patients with PD and healthy controls, there was significant parafoveal inner nuclear layer thinning, whereas other retinal layers, including the retinal nerve fiber layer, as well as total macular thicknesses were not different. In terms of visual hallucinations among the PD subgroups, only retinal nerve fiber layer thickness differed significantly, whereas total macular thickness and the thickness of other retinal layers did not differ. The retinal nerve fiber layer was thinnest in the group that had hallucinations without dementia, followed by the group that had hallucinations with dementia, and the group that had no hallucinations and no dementia. General ophthalmologic examinations did not reveal any significant correlation with hallucinations. There were no significant correlations between retinal thicknesses and duration or severity of PD and medication dosages. The results indicate that retinal nerve fiber layer thinning may be related to visual hallucination in nondemented patients with PD. Replication studies as well as further studies to elucidate the mechanism of thinning are warranted. © 2013 International Parkinson and Movement Disorder Society     

Visual object recognition and attention in Parkinson's disease patients with visual hallucinations

Visual hallucinations (VH) are common in Parkinson's disease (PD) and are hypothesized to be due to impaired visual perception and attention deficits. We investigated whether PD patients with VH showed attention deficits, a more specific impairment of higher order visual perception, or both. Forty‐two volunteers participated in this study, including 14 PD patients with VH, 14 PD patients without VH and 14 healthy controls (HC), matched for age, gender, education level and for level of executive function. We created movies with images of animals, people, and objects dynamically appearing out of random noise. Time until recognition of the image was recorded. Sustained attention was tested using the Test of Attentional Performance. PD patients with VH recognized all images but were significantly slower in image recognition than both PD patients without VH and HC. PD patients with VH showed decreased sustained attention compared to PD patients without VH who again performed worse than HC. In conclusion, the recognition of objects is intact in PD patients with VH; however, these patients where significantly slower in image recognition than patients without VH and HC, which was not explained by executive dysfunction. Both image recognition speed and sustained attention decline in PD, in a more progressive way if VH start to occur. © 2008 Movement Disorder Society     

Hypoperfusion of the visual pathway in parkinsonian patients with visual hallucinations.

Little is known about the developing mechanisms of visual hallucinations in Parkinson's disease. This study aimed to investigate perfusion changes in parkinsonian patients with visual hallucinations using n-isopropyl-p-[123I]iodoamphetamine ([123I]IMP) single photon emission computed tomography imaging. A total of 70 consecutive patients, including 31 patients with visual hallucinations, and 39 patients without hallucinations, participated in this study. Patients with severe cognitive impairment (Mini-Mental State Examination score < 20), nonvisual hallucinations, or confusion were excluded. We compared brain perfusion changes between the two groups. We found that hallucinatory patients had significant perfusion reductions in the bilateral inferior parietal lobule, inferior temporal gyrus, precuneus gyrus, and occipital cortex compared to nonhallucinatory patients. These results suggested that hypoperfusion of the visual pathway was closely related to visual hallucinations in Parkinson's disease.     

Cardiovascular dysautonomia in Parkinson's disease and multiple system atrophy

OBJECTIVES: To determine whether Parkinson's 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. PATIENTS AND METHODS: Seventeen patients with MSA, 39 with PD, and 25 healthy volunteers underwent 123I-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: 123I-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 123I-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 123I-MIBG radioactivity similar to MSA.     

Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson's disease.

In idiopathic Parkinson's disease (PD), different clinical subtypes are distinguished due to predominant motor symptoms: a tremor-dominant type (TDT), an akinetic rigid type (ART), and a mixed type (MT). We compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages of PD. We applied MIBG scintigraphy in 102 patients with PD. About 57 patients were at Hoehn and Yahr (H&Y) stage 1, 22 at H&Y stage 2, and 23 at H&Y stages 3 and 4. For quantification of myocardial MIBG uptake, the heart-to-mediastinum (H/M) count-ratio was calculated. At all H&Y stages, myocardial MIBG uptake was significantly higher in TDT patients than in ART or MT patients (P < 0.05; ANOVA). Furthermore, at each H&Y stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia (P < 0.05; Spearman's correlation) and rigidity (P < 0.05), but not with severity of resting or postural tremor. The significant correlation between myocardial sympathetic degeneration and severity of hypokinesia and rigidity suggests that myocardial sympathetic degeneration and hypokinetic-rigid symptoms develop in a closely coupled manner in early as well as advanced PD. No such correlation can be found between myocardial sympathetic degeneration and parkinsonian tremor.     

Visual hallucinations in Parkinson's disease: Theoretical models

One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson's disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson's disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading hypothetical frameworks for visual hallucinations in Parkinson's disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention. © 2014 International Parkinson and Movement Disorder Society     

123I‐metaiodobenzylguanidine scintigraphy in Parkinson's disease and related disorders

Autonomic dysfunction is common in Lewy body disorders (Parkinson's disease, Dementia with Lewy Bodies, Pure Autonomic Failure, and REM sleep disorder). The loss of post‐ganglionic myocardial sympathetic nerve fibers is a prominent feature of autonomic dysfunction in such disorders. ¹²³I‐metaiodobenzylguanidine (MIBG) scintigraphy that visualizes catecholaminergic terminals in vivo is a biomarker used to detect cardiac sympathetic degeneration. Abnormal MIBG uptake has been consistently reported in Lewy body disorders. Some studies agree in the notion that increasing bradykinesia is related with an incremental cardiac sympathetic denervation, whereas tremor is not closely linked to cardiac denervation. “Atypical” parkinsonian syndromes, including Multiple System Atrophy, Progressive Supranuclear Palsy, and others, show modest reductions of cardial MIBG uptake. MIBG scintigraphy is moderately sensitive and specific in differentiating Parkinson's disease from such syndromes. Conversely, its sensitivity and specificity might be better in cognitively impaired patients, helping differential diagnosis between Dementia with Lewy Bodies, and Alzheimer disease. Confounding factors (comorbidities, comedications) should be carefully controlled before analyzing MIBG scintigraphy. © 2009 Movement Disorder Society     

Visual hallucinations as REM sleep behavior disorders in patients with Parkinson's disease.

To clarify whether visual hallucinations in patients with Parkinson's disease (PD) are related to rapid eye movement (REM) sleep, nocturnal polysomnographic variables were compared between a group with hallucinations (hallucinators, n = 14) and a group without hallucinations (nonhallucinators, n = 8). A multiple sleep latency test (MSLT) was performed on 3 hallucinators, and the content of dreams during daytime REM sleep was investigated. The efficacy of clonazepam, a standard treatment choice for REM sleep behavior disorders, was investigated in 8 hallucinators. Nocturnal polysomnograms of the hallucinators showed a higher amount of stage 1-REM sleep with tonic electromyogram (stage 1-REM) than the nonhallucinators, and the reported occurrences of nocturnal hallucinations corresponded with the periods of stage REM or stage 1-REM in most hallucinators. The frequency of sleep onset REM periods (SOREMP) on the MSLT were pathologically high in the hallucinators, and the content of the dreams during the MSLT period was quite similar to their hallucinations. During clonazepam treatment, the frequency of hallucinatory symptoms decreased in 5 of 8 hallucinators. These results indicate that visual hallucinations in PD are likely to be related to a REM sleep disorder manifested as the appearance of both stage 1-REM during the night and SOREMP in the daytime.