Association of visual hallucinations with reduction of MIBG cardiac uptake in Parkinson's disease

doi:10.1016/j.jns.2007.07.017

Journal of the Neurological Sciences

Volume 264, Issues 1–2, 15 January 2008, Pages 22-26

https://doi.org/10.1016/j.jns.2007.07.017 Get rights and content

Abstract

Background

Postganglionic cardiac sympathetic denervation is evident in patients with Parkinson’s disease (PD) and iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) cardiac scintigraphy has proven to be a useful tool for diagnosis of PD.

Objective

To elucidate the factors associated with severity of cardiac sympathetic nerve dysfunction in PD patients.

Methods

We investigated 95 PD patients hospitalized in the Department of Neurology at Tottori University Hospital. ¹²³I-MIBG cardiac scintigraphy was performed on each patient and the early and delayed heart to mediastinum (H/M) ratios and washout rate (WR) of ¹²³I-MIBG cardiac scintigraphy were calculated. Independent predictive variables for parameters of ¹²³I-MIBG cardiac scintigraphy were analyzed by multivariate regression analysis.

Results

Multivariate regression analysis revealed that the presence of visual hallucinations (VH) and the patient’s age at the time of evaluation independently predicted the early or delayed H/M ratio. Analysis of covariance, adjusted for the age of the patients as covariates, revealed that the early and delayed H/M ratios of PD patients with VH but no dementia, as well as PD patients with dementia were significantly lower than the ratios in PD patients with no VH or dementia.

Conclusion

Cardiac sympathetic dysfunction may be associated with the presence of VH in PD patients.

Introduction

Metaiodobenzylguanidine (MIBG) is a physiological analogue of noradrenaline (norepinephrine), and ¹²³I-MIBG cardiac scintigraphy is used to evaluate postganglionic cardiac sympathetic innervation [1]. Recent studies have reported that reduction of cardiac MIBG uptake is associated with Lewy body diseases (LBDs) such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF), based on evidence of postganglionic cardiac sympathetic denervation in LBDs [2], [3], [4], [5]. Therefore, the heart to mediastinum (H/M) ratio of ¹²³I-MIBG cardiac scintigraphy has proven to be a useful diagnostic tool for LBDs. Although reduction of myocardial ¹²³I-MIBG uptake in PD is associated with onset age and severity of motor impairment [6], [7], it has not yet been clarified whether decreased cardiac uptake of MIBG is associated with neuropathological changes of the central nervous system and neuropsychiatric status in PD. In this study, we elucidated the clinical variables associated with parameters of ¹²³I-MIBG cardiac scintigraphy in PD patients.

Section snippets

Participants

Participants included 95 patients who were hospitalized for examination and treatment of Parkinson's symptoms at the Department of Neurology, Tottori University Hospital, Japan between April 2002 and December 2005. Patients were examined by at least two board certified neurologists of the Japanese Neurological Society. The clinical diagnosis of PD was based on the UK PD Society Brain Bank Criteria [8]. Diagnosis of PD with dementia (PDD) was based on the Diagnostic and Statistical Manual of

Results

Table 1 shows the clinical characteristics of patients with PD and PDD. There was a statistically significant difference in the age at evaluation, disease duration, Hoehn–Yahr stage, and MMSE score between the PD and PDD groups. However, there was no statistically significant difference in onset age, daily l-dopa dose, CV-RR, and ¹²³I-MIBG uptake. The prevalence of VH was 22 cases (33%) for PD patients and 23 cases (82%) for PDD patients, with a statistically significant difference between the

Discussion

PD is characterized by extrapyramidal symptoms (tremor, rigidity and bradykinesia) and various psychotic symptoms that occur over the clinical course. VH are one of the most common psychotic symptoms in PD, occurring in approximately 30 to 60% of PD patients [10], [11], [12], [13]. While VH in PD patients have been considered an adverse event of antiparkinsonian therapy, recent studies have reported that VH might be a component of PD symptoms [13], [14], [15]. Dementia is also one of the most

Acknowledgments

We would like to thank the staff of the Department of Neurology, Tottori University for their help in recruiting patients. This work was supported in part by the Research Committee of CNS Degenerative Disease, Ministry of Health and Welfare of Japan.

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Cognitive impairment is one of the most disabling non-motor symptoms associated with Parkinson's disease (PD) [1]. Cardiac iodine-123-meta-iodobenzylguanidine (MIBG) uptake can reveal sympathetic cardiac denervation caused by Lewy bodies (LB) [2] and, reduced uptake is correlated with various non-motor symptoms of PD including cognition, orthostatic hypotension, hyposmia, and rapid eye movement behavior disorder (RBD) [3–7]. Of interest, patients affected with dementia with Lewy bodies (DLB) and presenting with mild cognitive impairment can exhibit reduced cardiac MIBG uptake [8–10], suggesting that the reduction in uptake reflects wider extension of alpha-synuclein pathology [11].
Postganglionic cardiac sympathetic denervation is evident in patients with early-stage Parkinson's disease (PD). Cardiac iodine-123-meta-iodobenzylguanidine (MIBG) uptake is correlated with the non-motor symptoms of PD, suggesting that low cardiac MIBG uptake may reflect wider alpha-synuclein pathology. In addition, low cardiac MIBG could be related to orthostatic hypotension in PD, which may affect cognition. However, the prognostic validity of baseline MIBG scintigraphy in terms of the risk of subsequent dementia remains unclear. We investigated whether cardiac MIBG uptake was associated with a later risk of dementia.
We retrospectively enrolled 93 drug-naive patients with de novo PD who underwent MIBG scanning on initial evaluation. The patients visited our outpatient clinic every 3–6 months and were followed-up for a minimum of 4 years from the time they were begun on dopaminergic medication. The predictive powers of baseline MIBG cardiac scintigraphic data in terms of dementia development were evaluated using Cox's proportional hazard models.
During a mean follow-up period of 6.7 years, 27 patients with PD (29.0%) developed dementia. These patients had less baseline MIBG uptake than did others (delayed H/M ratios: 1.19 vs. 1.31). Multivariate Cox's proportional hazard modeling revealed that both MIBG uptake (hazard ratio [HR] 3.40; p = 0.004) and age (HR 1.08, p = 0.01) significantly predicted dementia development.
A reduction in cardiac MIBG uptake by PD patients may be associated with a subsequent risk of dementia; reduced uptake may reflect wider extension of alpha-synuclein pathology in PD.
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Autonomic dysfunction and increased sepsis mortality are associated with loss of heart rate variability and chronic neurodegeneration [165,166]. Autonomic dysfunction is seen in dementias, particularly in individuals with visual hallucinations who are characterized by an aggressive disease course [167,168]. In addition to its role in immune homeostasis, the ANS is involved in reflexive monitoring and control in the cardiovascular system.
Retrospective data are presented to support a spectrum of early Alzheimer’s disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.
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Some studies have shown an association with other psychiatric disorders, particularly depression (Holroyd et al., 2001; Sanchez-Ramos et al., 1996) however results are inconsistent. Autonomic dysfunction has also been associated with the presence of VH in PD (Kitayama et al., 2008; Williams and Lees, 2005). Severe olfactory impairment has also been associated with increased risk of neuropsychiatric features in PD, including cognitive decline and visual hallucinations (Stephenson et al., 2010).
Psychiatric symptoms are important non-motor features in PD, which occur at high frequency and have significant impact on health related quality of life. This review concentrates on the prevalence, pathophysiology, diagnosis and treatment of depression, anxiety, apathy and psychosis. The pathophysiology of these disorders is complex, reflecting the widespread brainstem and cortical pathology in PD, with involvement of several neurotransmitters, including dopaminergic, serotonergic, noradrenergic and cholinergic systems. The diagnosis of psychiatric conditions, in particular affective disorders, is challenging because of the overlap of somatic features of psychiatric disorders and underlying movement disorder. The pathogenesis is likely to differ considerably from non-PD patients, and treatments used in general psychiatry services may not be as effective in PD and will require clearer clarification in well-designed clinical studies. Management strategies include adjustment of dopaminergic medication, use of psychotropic treatments and behavioural and psychological approaches. However, the future challenge will be to develop treatments developed specifically for the pathogenesis of these disorders in PD.
Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson's disease
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Hallucinations experienced by PD patients have been postulated to occur via the following mechanisms: dopaminergic over-activity in the limbic system and cerebral cortices [18]; an imbalance with cholinergic neurotransmission [19]; dysfunction of the frontal areas associated with the control of attention [20]; PD-associated retinopathy [21]; decline of both image recognition speed and sustained attention [22]; alterations of brainstem sleep-wake and dream regulation [23]. Hallucinations are also associated with myocardial sympathetic dysfunction in PD [24]. Dysregulation of β1-adrenergic system in PD tends to cause myocardial tachycardia [25], which may increase the myocardial oxidative stress.
Oxidative stress is causally associated with the pathogenesis of Parkinson’s disease (PD). Oxygen generates a large amount of reactive oxygen species (ROS). ROS including hydroxyl radicals and H₂O₂ react with guanine residues in DNA and produce 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG serves as a biomarker for oxidative stress in various diseases.
We investigated urinary 8-OHdG levels in 61 PD patients and 28 normal subjects to evaluate the correlation with various clinical features. We quantified disease severity using the Unified Parkinson’s Disease Rating Scale for motor symptoms (UPDRS part 3), the Mini-Mental State Examination (MMSE) for mental function, and the Tottori University Hallucination Rating Scale (TUHARS) for quantifying hallucinations.
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To clarify whether the existence of RBD accelerates autonomic dysfunction in PD, we investigated the association between MIBG scintigraphic findings and RBD measures among non-dementia PD patients.
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Association of visual hallucinations with reduction of MIBG cardiac uptake in Parkinson's disease

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Participants

Results

Discussion

Acknowledgments

Parkinsonism Relat Disord

J Neurol Sci

Lancet Neurol

J Am Coll Cardiol

Myocardial imaging with a radioiodinated norepinephrine storage analog

J Nucl Med

(123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease

J Neurol Neurosurg Psychiatry

Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD

Neurology

Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson's disease

J Neurol Neurosurg Psychiatry

Onset age and severity of motor impairment are associated with reduction of myocardial 123I-MIBG uptake in Parkinson's disease

J Neurol Neurosurg Psychiatry

Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases

J Neurol Neurosurg Psychiatry

Psychosis in Parkinson's disease

Mov Disord

Repeated visual hallucinations in Parkinson's disease as disturbed external/internal perceptions: focused review and a new integrative model

Mov Disord

Hallucinations in Parkinson disease in the prelevodopa era

Neurology