Satoshi Orimo

123 I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease

OBJECTIVES 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is clinically used to estimate local myocardial sympathetic nerve damage in some forms of heart disease, autonomic nerve disturbance in diabetic neuropathy, and disturbance of the autonomic nervous system in neurodegenerative disease. In the present study, examinations were performed to clarify (1) the proportion of cardiac sympathetic nerve disturbance in Parkinson’s disease, (2) the usefulness of 123I-MIBG myocardial scintigraphy to detect sympathetic nerve disturbances compared with autonomic function tests, (3) cardiac function in patients who have a decreased MIBG uptake in 123I-MIBG myocardial scintigraphy, (4) the usefulness of 123I-MIBG myocardial scintigraphy to differentiate Parkinson’s disease from the other neurological diseases mimicking it. METHODS 123I-MIBG myocardial scintigraphy was performed, together with autonomic function tests and cardiac examinations in 46 patients with Parkinson’s disease and 25 patients with vascular parkinsonism, essential tremor, or multiple system atrophy. RESULTS In an anterior image study, the average count per pixel in heart to mediastinum (H/M) ratio decreased in 80% of the patients with Parkinson’s disease in the early phase and 84% in the late phase. The mean H/M ratio in Parkinson’s disease was significantly lower than that in controls and the other diseases. The H/M ratio tended to decrease with the disease progression. In almost half of the patients in Hoehn and Yahr stage I, the H/M ratio was already decreased. The sympathetic skin response in upper and lower limbs, head up tilt test, and coefficient of variation of R-R interval were abnormal in 17%, 31%, 30%, and 17% of the patients, respectively. All the patients with abnormal autonomic functions were in Hoehn and Yahr stage III, IV, or V. Echocardiography showed normal left ventricular function. Twenty four hour Holter electrocardiography detected no serious arrhythmias except for one patient with non-sustained ventricular tachycardia. CONCLUSION 123I-MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in Parkinson’s disease and might give useful diagnostic information to differentiate vascular parkinsonism, essential tremor, and multiple system atrophy from Parkinson’s disease.

Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson's disease

Decreased cardiac uptake of meta‐iodobenzylguanidine (MIBG) on [123I] MIBG myocardial scintigraphy has been reported in the early stages of Parkinson’s disease (PD), which suggests involvement of the cardiac sympathetic nerve in the early disease process of PD. For confirmation, we immunohistochemically examined cardiac tissue, sympathetic ganglia and medulla oblongata of 20 patients with incidental Lewy body disease (ILBD), which is thought to be a presymptomatic stage of PD, and 10 control subjects, using antibodies against tyrosine hydroxylase (TH) and neurofilament (NF). Immunoreactive nerve fibers of fascicles in the epicardium were well preserved in 10 of the 20 patients with ILBD and in the control subjects. In contrast, TH‐immunoreactive nerve fibers had nearly disappeared in six subjects and were moderately decreased in four of the 20 patients with ILBD. Neuronal cell loss in the dorsal vagal nucleus and the sympathetic ganglia was not detectable in any of the ILBD patients examined. These findings suggest that degeneration of the cardiac sympathetic nerve begins in the early disease process of PD and that it occurs before neuronal cell loss in the dorsal vagal nucleus.

Profound Cardiac Sympathetic Denervation Occurs in Parkinson Disease

In the last few years, cardiac sympathetic dysfunction in Parkinson disease (PD) has been postulated on the basis of decreased cardiac uptake of sympathoneural imaging tracers. However, the pathological substrate for the dysfunction remains to be established. We examined the left ventricular anterior wall from postmortem specimens with immunohistochemical staining for tyrosine hydroxylase (TH), neurofilament (NF) and S‐100 protein in PD patients and control subjects, and quantified the immunoreactive areas. As TH‐immunoreactive axons nearly disappeared and NF‐immunoreactive axons drastically decreased in number, the morphological degeneration of the cardiac sympathetic nerves in PD was confirmed. Quantitative analysis showed that sympathetic nerves were preferentially involved. Triple immunofluorolabeling for NF, TH, and myelin basic protein showed clearly the profound involvement of sympathetic axons in PD. The extent of involvement of the cardiac sympathetic nerves seems likely to be equivalent to that in the central nervous system, including the nigrostriatal dopaminergic system. PD affects the cardiac sympathetic nervous system profoundly as well as nigrostriatal dopaminergic system.

Sympathetic cardiac denervation in Parkinson's disease and pure autonomic failure but not in multiple system atrophy.

Three neurodegenerative diseases causing primary autonomic failure are pure autonomic failure (PAF), Parkinsons disease (PD), and multiple system atrophy (MSA). Differential diagnoses among these diseases are often difficult especially in early disease stage. For example, it may be difficult to determine whether a patient with parkinsonism and autonomic failure has PD or MSA. Recently, a decrease in myocardial uptake of meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, has been reported in PD but not in MSA using [123I]MIBG myocardial scintigraphy.1 This new imaging approach is thought to be of significance in the diagnosis and characterisation of akinetic rigid syndromes, especially PD. After that, we reported severe loss of cardiac sympathetic nerves in one patient with PD but not in one patient with MSA, which accounts for a difference in myocardial uptake of MIBG between PD and MSA.2 However, our observation was based on the study in only a single patient of each disease. In this study, we immunohistochemically examined the heart tissues from four patients with PD, three patients with MSA, and one patient with PAF, and showed the involvement of postganglionic cardiac sympathetic nerves in PD and PAF …

Cognitive status correlates with white matter alteration in Parkinson's disease.

Patients with Parkinsons disease (PD) can develop mild cognitive impairment (PD‐MCI), frequently progressing to dementia (PDD). Here, we aimed to elucidate the relationship between white matter alteration and cognitive status in PD and dementia with Lewy bodies (DLB) by using diffusion tensor imaging. We also compared the progression patterns of white and gray matter and the cerebral perfusion. We enrolled patients with PD cognitively normal (PD‐CogNL, n = 32), PD‐MCI (n = 28), PDD (n = 25), DLB (n = 29), and age‐ and sex‐matched healthy control subjects (n = 40). Fractional anisotropy (FA) map of a patient group was compared with that of control subjects by using tract‐based spatial statistics. For the patient cohort, intersubject voxel‐wise correlation was performed between FA values and Mini‐Mental Status Examination (MMSE) scores. We also evaluated the gray matter and the cerebral perfusion by conducting a voxel‐based analysis. There were significantly decreased FA values in many major tracts in patients with PD‐MCI, PDD, and DLB, but not in PD‐CogNL, compared with control subjects. FA values in the certain white matter areas, particularly the bilateral parietal white matter, were significantly correlated with MMSE scores in patients with PD. Patients with PDD and DLB had diffuse gray matter atrophy. All patient groups had occipital and posterior parietal hypoperfusion when compared with control subjects. Our results suggest that white matter damage underlies cognitive impairment in PD, and cognitive impairment in PD progresses with functional alteration (hypoperfusion) followed by structural alterations in which white matter alteration precedes gray matter atrophy. Hum Brain Mapp, 2011.

Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [123I] MIBG myocardial scintigraphy, a sensitive biological marker for Parkinson’s disease (PD), is related to cardiac sympathetic denervation in patients with PD. A slight decrease in cardiac uptake of MIBG has also been reported in some patients with multiple system atrophy (MSA). However, the pathophysiological mechanism accounting for the slight decrease in MIBG uptake in MSA remains to be elucidated. For confirmation, we examined cardiac tissue and sympathetic ganglia from patients with MSA. We immunohistochemically examined each specimen of 15 patients with MSA together with 10 control subjects using antibodies against tyrosine hydroxylase (TH) and neurofilament (NF). The number of TH-immunoreactive nerve fibers in the epicardium was preserved in 8 of 15 patients with MSA as well as in 10 control subjects. The number of TH-immunoreactive, but not of NF-immunoreactive nerve fibers in the epicardium was mildly or moderately decreased in six patients with MSA, of whom four showed a decrease of TH immunoreactivity in the neuronal somata in the sympathetic ganglia. Moreover, TH- and NF-immunoreactive nerve fibers almost entirely disappeared in the heart of one patient with MSA, in whom Lewy body pathology was present in the sympathetic ganglia. These findings suggest that mild degeneration of the cardiac sympathetic nerve can occur in MSA which is closely related to the pathological change of neurons in the sympathetic ganglia, accounting for the slight decrease in cardiac uptake of MIBG. Moreover, concurrent Lewy body pathology in the sympathetic ganglia might accelerate cardiac sympathetic denervation even in MSA.

Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain

Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson’s disease, neuronal α-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time. In multiple system atrophy, numerous glial cytoplasmic inclusions composed of filamentous α-synuclein are widely distributed in the CNS, while α-synuclein accumulation is minimal in the sympathetic ganglia and is restricted to neurons. Neurofibrillary tangles can occur in the sympathetic and spinal ganglia in tauopathy, although they appear to develop independently of cerebral Alzheimer’s disease pathology. In amyotrophic lateral sclerosis, neuronal loss with TDP-43-positive neuronal cytoplasmic inclusions in the spinal ganglia is more frequent than previously thought. Peripheral ganglia and visceral organs are also involved in polyglutamine diseases. Further elucidation and characterization of PNS lesions will have implications for intravital biopsy diagnosis in neurodegenerative proteinopathy, particularly in Parkinson’s disease.

Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2

We performed [123I] MIBG myocardial scintigraphy in two of three patients with PARK2 from unrelated families and examined the heart tissues from the three patients immunohistochemically using an antibody against tyrosine hydroxylase (TH) to see whether cardiac sympathetic nerve is involved. Cardiac uptake of MIBG was normal except for a slight decrease in the late phase in one of the patients. Postmortem examination revealed that TH‐immunoreactive nerve fibers in the epicardium were well preserved in all three patients. The present study confirmed that cardiac sympathetic nerve is well preserved in PARK2 with a homozygous exon deletion, which accounts for normal cardiac uptake of MIBG. Moreover, normal cardiac uptake of MIBG might be of potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa‐responsive Parkinsonism, as in PARK2.

Spreading of amyotrophic lateral sclerosis lesions—multifocal hits and local propagation?

Objective To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the ‘single seed and simple propagation’ hypothesis). Methods Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)—that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)—were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Results Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. Conclusions In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the ‘single seed and simple propagation’ hypothesis alone. We propose a ‘multifocal hits and local propagation’ hypothesis instead.

Three-Layered Structure Shared Between Lewy Bodies and Lewy Neurites—Three-Dimensional Reconstruction of Triple-Labeled Sections

Lewy bodies (LBs) and Lewy neurites (LNs) are the hallmarks of Parkinsons disease (PD). Although LBs and LNs, frequently coexistent, share some histological properties, their appearances are quite different under conventional two‐dimensional observation. In order to clarify how these apparently different structures (LBs and LNs) are related during their formation, we performed three‐dimensional observation on post‐mortem brainstem tissues with PD. Sixty‐µm thick floating sections were multi‐immunofluorolabeled for α‐synuclein (αS), ubiquitin (Ub) and neurofilament (NF). Serial confocal images were reconstructed with software. External three‐dimensional configuration of LBs, double‐labeled for αS and NF, exhibited frequent continuity with LNs (70%). Internally, αS and Ub formed the three‐dimensional concentric inner layers and NF rimmed these inner layers. This layered structure was shared among spherical LBs, rod‐shaped LNs and even convoluted forms of LBs/LNs. Furthermore, each layer exhibited continuity without interruption even in the convoluted form and around its junction to spherical LBs. This three‐layered structure shared among various Lewy pathologies and their layered continuity on three‐dimensional basis favor the hypothesis that LNs evolve into LBs. Besides progression from pale bodies to LBs, structural evolution from LNs into LBs may provide an alternative explanation for the variability of αS deposits and their interrelation.