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PubMed2004

Abnormal motor behavior during sleep.

Abnormal motor behaviors during sleep can be classified into four categories, ranging from myoclonic jerks to complex and integrated motor behaviors There have been recent developments in several of these conditions, in particular restless legs syndrome (RLS) and rapid-eye-movement sleep behavior disorder (RBD). RLS is one of the major causes of insomnia. Familial aggregation of RLS has been demonstrated by several groups, and molecular genetics studies have suggested the presence of susceptibility genes on chromosomes 12q and 14q. Pharmacologic and brain imaging studies suggest the involvement of dopaminergic mechanisms in RLS, but recent work has focused on brain iron metabolism. Studies indicate that RBD patients may eventually develop Parkinson's disease (PD). Conversely, RBD has been found in patients already diagnosed with PD. Single-photon emission computed tomography and positron emission tomography studies have shown a decrease in binding to presynaptic dopamine transporter in both idiopathic RBD and PD. Patients with RBD (associated or unassociated with PD) also have neuropsychological deficits. RBD may therefore represent the prodrome of a neurodegenerative disease leading to multiple system atrophy and Lewy body dementia. Understanding the underlying pathophysiology of abnormal sleep motor behaviors may prove useful in the management of insomnia.

Brain↗

PubMed2006

Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases.

Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is characterised by loss of muscular atonia and prominent motor behaviours during REM sleep. RBD can cause sleep disruption and severe injuries for the patient or bed partner. The disorder is strongly associated with neurodegenerative diseases, such as multiple-system atrophy, Parkinson's disease, dementia with Lewy bodies, and progressive supranuclear palsy. In many cases, the symptoms of RBD precede other symptoms of these neurodegenerative disorders by several years. Furthermore, several recent studies have shown that RBD is associated with abnormalities of electroencephalographic activity, cerebral blood flow, and cognitive, perceptual, and autonomic functions. RBD might be a stage in the development of neurodegenerative disorders and increased awareness of this could lead to substantial advances in knowledge of mechanisms, diagnosis, and treatment of neurodegenerative disorders.

Brain↗

PubMed2006

Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study.

BACKGROUND: Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviours related to unpleasant dreams and loss of muscle atonia during REM sleep. RBD may be idiopathic or associated with neurological disease. Available data suggest that in some cases RBD might be the initial manifestation of a neurodegenerative disease. We sought to determine the frequency and nature of neurological disorders developing in patients diagnosed with idiopathic RBD at our sleep centre. METHODS: We retrospectively assessed 44 consecutive patients (39 men and five women with a mean age of 74 years), with at least 2 years of clinical follow-up after a diagnosis of idiopathic RBD, through a detailed clinical history, complete neurological examination, rating scales of parkinsonism, and neuropsychological tests. FINDINGS: 20 (45%) patients developed a neurological disorder after a mean of 11.5 years from the reported onset of RBD and a mean follow-up of 5.1 years from the diagnosis of idiopathic RBD at our sleep centre. Emerging disorders were Parkinson's disease in nine patients, dementia with Lewy bodies in six, multiple system atrophy with predominant cerebellar syndrome in one, and mild cognitive impairment in four in whom visuospatial dysfunction was prominent. Patients with longer clinical follow-up developed a neurological disease (OR 1.512, 95% CI 1.105-2.069; p=0.010). INTERPRETATION: Our study indicates that in people presenting to sleep centres, RBD often antedates the development of a neurodegenerative disorder. Close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative disease. This finding may be of great interest when early effective treatment strategies and neuroprotective drugs become available.

Aged↗

PubMed1999

Differential diagnosis of parkinsonism.

The diagnosis of Parkinson's disease is predominantly clinical, based on a combination of the cardinal features of tremor, bradykinesia and rigidity. The differential essentially lies between other conditions resulting in tremor, of which essential tremor is the commonest, and other akinetic-rigid syndromes. These include progressive supranuclear palsy, multiple system atrophy, toxins and other degenerative disorders, including diffuse Lewy body disease and corticobasal degeneration. The key clinical features of these disorders and a practical diagnostic approach are briefly reviewed in this article.

Diagnosis, Differential↗

PubMed1993

Glutamate dehydrogenase deficiency in Machado-Joseph disease.

We studied the activity of glutamate dehydrogenase (GDH) in leukocytes from 23 patients with dominantly inherited ataxia. All the patients were assessed with a rating scale for ataxias and met the clinical criteria for the diagnosis of Machado-Joseph disease. The mean age of onset of symptoms was 37.8, SD 13.4 years and the duration of the disease was 7.4, SD 4.9. Leukocyte GDH activity was significantly decreased (p < 0.001) when compared to 20 normal controls. These data extend previous reports indicating that a GDH deficiency is present in peripheral tissues from some patients with spinocerebellar degenerations. Furthermore, this study suggests that a genetic deficiency of GDH may underlie some forms of dominant ataxias; this deficiency may be marked in patients with Machado-Joseph disease and is not specific for any type of multiple system atrophy.

Adolescent↗

PubMed2001

Membrane binding and self-association of alpha-synucleins.

Although its function is unknown, alpha-synuclein is widely distributed in neural tissue and is the major component in the pathological aggregates found in patients with Parkinson's disease, Alzheimer's disease, Down's syndrome, and multiple system atrophy. In this report, we have quantified the binding alpha-synucleins to lipid membranes. In contrast to previous studies, we find, using real time equilibrium fluorescence methods, that alpha-synuclein binds strongly to large, unilamellar vesicles with either anionic or zwitterionic headgroups. Membrane binding is also strong for beta-synuclein, phosphorylated alpha-synuclein, and a synuclein mutant that is associated with familial Parkinson's disease. In solution at less than 400 nM, synuclein has a tendency to undergo concentration-dependent oligomerization as determined by changes in intrinsic fluorescence and fluorescence resonance energy transfer. Above this concentration, the protein begins to aggregate into structures visible by light scattering. Although membrane binding does not affect the secondary structure of alpha-synuclein, it greatly inhibits the ability of this protein to self-associate. Taken together, our results indicate that pathological conditions may be associated with a disruption in synuclein-membrane interactions.

Blotting, Western↗

PubMed2003

Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes.

Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of alpha-synuclein are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple systemic atrophy. The molecular mechanisms underlying the aggregation of alpha-synuclein into such filamentous inclusions remain unknown, although many factors have been implicated, including interactions with lipid membranes. To model the effects of membrane fields on alpha-synuclein, we analyzed the structural and fibrillation properties of this protein in mixtures of water with simple and fluorinated alcohols. All solvents that were studied induced folding of alpha-synuclein, with the common first stage being formation of a partially folded intermediate with an enhanced propensity to fibrillate. Protein fibrillation was completely inhibited due to formation of beta-structure-enriched oligomers with high concentrations of methanol, ethanol, and propanol and moderate concentrations of trifluoroethanol (TFE), or because of the appearance of a highly alpha-helical conformation at high TFE and hexafluoro-2-propanol concentrations. At least to some extent, these conformational effects mimic those observed in the presence of phospholipid vesicles, and can explain some of the observed effects of membranes on alpha-synuclein fibrillation.

Alcohols↗

PubMed2005

Ubiquitination of alpha-synuclein.

Filamentous alpha-synuclein depositions are the defining hallmarks of a subset of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. We previously reported that alpha-synuclein in those brains are extensively phosphorylated at Ser129 [Fujiwara et al. (2002) Nat. Cell Biol. 4, 160-164] and also partially ubiquitinated [Hasegawa et al. (2002) J. Biol. Chem. 277, 49071-49076]. Here, we investigate ubiquitination of alpha-synuclein in vitro and in vivo and report the ubiquitination sites and the effects of familial PD-linked mutations, phosphorylation, and fibril formation on ubiquitination. Protein-sequence analysis revealed that Lys21, Lys23, Lys32, and Lys34 within the repeats in the amino-terminal half are liable to ubiquitination in vitro. A site-directed mutagensis study confirmed that these are the major ubiquitination sites. A53T and A30P mutations had no significant effect on ubiquitination. Similarly, phosphorylation of alpha-synuclein at Ser129 did not affect ubiquitination. Notably, we show that assembled, filamentous alpha-synuclein is less ubiquitinated than the soluble form and that the major ubiquitination sites are localized to Lys6, Lys10, and Lys12 at the amino-terminal region of filamentous alpha-synuclein. Furthermore, we successfully detected ubiquitination of alpha-synuclein in 293T cells by cotransfection with alpha-synuclein and ubiquitin. The in vivo ubiquitination sites were found to be identical to those in filamentous alpha-synuclein. PD-linked mutations and phosphorylation at Ser129 had no effects on ubiquitination of alpha-synuclein in vivo. These data may have implications for the mechanisms of the formation of alpha-synuclein deposits in alpha-synucleinopathy brains.

Binding Sites↗

PubMed2006

Synuclein proteins of the pufferfish Fugu rubripes: sequences and functional characterization.

In humans, three genes encode the related alpha-, beta-, and gamma-synucleins, which function as lipid-binding proteins in vitro. They are being widely studied, mainly because of the central involvement of alpha-synuclein in a number of neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In these diseases, the normally soluble alpha-synuclein assembles into abnormal filaments. Here, we have identified and characterized the synuclein gene family from the pufferfish Fugu rubripes. It consists of four genes, which encode alpha-, beta-, gamma1-, and gamma2-synucleins. They range from 113 to 127 amino acids in length and share many of the characteristics of human synucleins, including the presence of imperfect amino-terminal repeats of 11 amino acids, a hydrophobic middle region, and a negatively charged carboxy-terminus. All four synucleins are expressed in the Fugu brain. Recombinant Fugu synucleins exhibited differential liposome binding, which was strongest for alpha-synuclein, followed by beta-, gamma2-, and gamma1-synucleins. In assembly experiments, Fugu alpha-, gamma1-, and gamma2-synucleins formed filaments more readily than human alpha-synuclein. Fugu beta-synuclein, by contrast, failed to assemble in bulk. Filament assembly of synucleins was directly proportional to their degree of hydrophobicity and their tendency to form beta-sheet structure, and correlated inversely with their net charge.

Amino Acid Sequence↗

PubMed2002

[Autonomic disorders in idiopathic Parkinson syndrome: diagnostic relevance and therapeutic possibilities].

Involvement of the autonomic nervous system in Parkinson's disease (PD) demonstrates the multiple system character of this disease exceeding the extrapyramidal system. Forty to sixty percent of patients with PD suffer from symptoms of autonomic failure impairing their quality of life. Autonomic failure in PD is caused by damage to the postganglionic part of the autonomic nervous system. Scintigraphy with radiolabeled metaiodobenzylguanidin (MIBG) provides evidence of autonomic involvement at an early stage of the disease and enables an early differential diagnosis of PD versus other neurodegenerative disorders. Sensitivity to identify PD versus multiple system atrophy is 89.7%, specificity in 94.6%. Orthostatic hypotension is a frequently overlooked symptom in PD. Diagnosis and cause of orthostatic hypotension can be identified with clinical methods. There are effective physical and pharmacological treatments to improve symptoms.

Autonomic Nervous System Diseases↗

PubMed2002

Ambulatory blood pressure monitoring in patients with spinocerebellar degeneration.

OBJECTIVES: The aim of this study was to demonstrate circadian blood pressure trends and to evaluate autonomic function in patients with spinocerebellar degeneration (SCD). MATERIALS AND METHODS: We performed 24-h ambulatory blood pressure monitoring (ABPM) on 10 patients from seven Japanese families with spinocerebellar ataxia type 6 (SCA6), 10 patients with idiopathic cerebellar ataxia (ICA), eight patients with multiple system atrophy (MSA) suffering from cerebellar MSA (MSA-C), and 12 age- and gender-matched normal subjects. We also evaluated autonomic function in these patients. RESULTS: Three SCA6 patients (30%), six ICA patients (60%), eight MSA-C patients (100%) and four normal subjects (33%) were non-dippers. The nocturnal reduction rate of blood pressure in MSA patients was significantly less than those in normal subjects, SCA6 patients and ICA patients. There were no abnormal findings in any patient with SCA6 in autonomic function tests. All dipper patients exhibited normal findings on autonomic function tests. This is the first report of ABPM in patients with SCD. CONCLUSIONS: Blunted reduction of nocturnal blood pressure may be associated with autonomic dysfunction in patients with SCD.

Aged↗

PubMed1990

A two-compartment description and kinetic procedure for measuring regional cerebral [11C]nomifensine uptake using positron emission tomography.

S-[11C]Nomifensine (S-[11C]NMF) is a positron-emitting tracer suitable for positron emission tomography, which binds to both dopaminergic and noradrenergic reuptake sites in the striatum and the thalamus. Modelling of the cerebral distribution of this drug has been hampered by the rapid appearance of glucuronide metabolites in the plasma, which do not cross the blood--brain barrier. To date, [11C]NMF uptake has simply been expressed as regional versus nonspecific cerebellar activity ratios. We have calculated a "free" NMF input curve from red cell activity curves, using the fact that the free drug rapidly equilibrates between red cells and plasma, while glucuronides do not enter red cells. With this free [11C]NMF input function, all regional cerebral uptake curves could be fitted to a conventional two-compartment model, defining tracer distribution in terms of [11C]NMF regional volume of distribution. Assuming that the cerebellar volume of distribution of [11C]NMF represents the nonspecific volume of distribution of the tracer in striatum and thalamus, we have calculated an equilibrium partition coefficient for [11C]NMF between freely exchanging specific and nonspecific compartments in these regions, representing its "binding potential" to dopaminergic or noradrenergic uptake sites (or complexes). This partition coefficient was lower in the striatum when the racemate rather than the active S-enantiomer of [11C]NMF was administered. In the striatum of patients suffering from Parkinson's disease and multiple-system atrophy, the specific compartmentation of S-[11C]NMF was significantly decreased compared with that of age-matched volunteers.

Brain↗

PubMed2002

alpha-Synuclein is phosphorylated in synucleinopathy lesions.

The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

Aged↗

PubMed1981

Endogenous agonist regulation of alpha-adrenoceptors in man.

1. Plasma noradrenaline concentrations and platelet alpha-receptor properties were measured in 14 normal subjects, five phaeochromocytoma patients and nine patients with multiple system atrophy and sympathetic nervous system degeneration (MSA). 2. Plasma noradrenaline concentrations in phaeochromocytoma were 10- to 20-times greater than those of normal subjects and one-fifth to one-half of normal in MSA patients. 3. Platelet alpha-receptor numbers were increased in MSA and decreased in phaeochromocytoma compared with normal subjects. There was no change in platelet alpha-receptor affinity in either group. 4. The inverse relationship between alpha-receptor numbers and plasma noradrenaline concentrations may reflect regulation of alpha-receptor number by endogenous adrenergic agonist concentrations in man.

Adrenal Gland Neoplasms↗

PubMed1997

Difficult defaecation and/or faecal incontinence as a presenting feature of neurologic disorders in four patients.

We report four cases of difficult defaecation and/or faecal incontinence revealing a neurologic disease. These anorectal symptoms were associated with urinary disorders, but urinary symptoms always appeared several years after anorectal complaints. Clinical neurologic examination immediately led us to suspect a neurologic aetiology in two patients with the following signs: perineal hypoesthesia, absence of voluntary anal contraction and anal reflexes in one subject (final diagnosis: L1 neurinoma), and in the other a weakness in both thighs with absent tendon reflexes in the four limbs (final diagnosis: amiodarone neuropathy). In the two other patients with multiple cerebral infarction or multiple system atrophy, the neurologic aetiology was suspected on the absence of anal voluntary contraction contrasting with a normal perineal anatomy, but the final diagnosis was made only two years later when orthostatic arterial hypotension occurred.

Aged↗

PubMed2003

Alpha-synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification.

alpha-Synuclein is known to be a major constituent of the Lewy bodies (LBs) in Parkinson's disease (PD) and the neuronal and glial cytoplasmic inclusions (NCIs, GCIs) in multiple system atrophy. alpha-Synuclein-positive inclusions such as LBs, NCIs and GCIs sometimes show colocalization with tau-positive neurofilaments. Studies using alpha-synuclein immunohistochemistry have often found LBs in the amygdala of patients with familial or sporadic Alzheimer's disease (AD), as well as in patients with Down's syndrome and AD. However, no studies have reported alpha-synuclein-positive structures in cases of diffuse neurofibrillary tangles with calcification (DNTC), which is characterized by numerous neurofibrillary tangles (NFTs) throughout the cerebral cortex but few, if any, senile plaques. We investigated the distribution of alpha-synuclein-positive structures in two cases of DNTC: a 65-year-old woman (brain weight, 850 g) and a 75-year-old woman (brain weight, 800 g). In both cases, severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, alpha-synuclein-positive intracytoplasmic inclusions and neurites were found in the superior temporal lobe (within the temporal pole), amygdala, parahippocampus, entorhinal cortex and insula, the regions most affected by the NFTs. alpha-Synuclein-positive intracytoplasmic inclusions were rare or absent in other regions of the cerebral cortex and brainstem. This distribution pattern differs from that of PD or dementia with LBs. Our findings suggest that the accumulation pattern of alpha-synuclein is a pathological feature of DNTC, and that DNTC is associated with accumulation of both tau and alpha-synuclein.

Aged↗

PubMed2000

Encephalomyelitis, brain tumors, neuromuscular diseases and miscellaneous disorders.

Japanese neuropathologists have accomplished and contributed to a considerable number of achievements, and some of these are cited in other articles in this issue. Several of these achievements as well as other miscellaneous discoveries are briefly summarized in the present paper. Specifically these relate to rabies postvaccinal encephalomyelitis, experimental allergic encephalomyelitis, brain tumor research, neuromuscular disorders, schizophrenia, viral infections, glial inclusion body in multiple system atrophy, and the neurobiology of glia.

Brain Neoplasms↗

PubMed1997

How to recognize patients with parkinsonism who should not have urological surgery.

OBJECTIVE: To examine whether there are urogenital criteria that the urologist could apply to a patient with idiopathic Parkinson's disease (IPD) and bladder symptoms, and so avoid operating on patients with multiple system atrophy (MSA). PATIENTS AND METHODS: The clinical features of 52 patients with probable MSA and 41 patients with IPD were studied retrospectively with particular attention to the nature of lower urinary tract symptoms and erectile dysfunction in relation to the onset of parkinsonism. Anal sphincter electromyography (EMG) was recorded in all the patients with MSA and in 12 of the patients with IPD. RESULTS: Of the patients with MSA, 60% had urinary symptoms preceding or presenting with IPD but in 94% of the patients with IPD the neurological diagnosis preceded the onset of urogenital symptoms. Most of the patients with MSA (73%) had troublesome urinary incontinence whereas the majority of those with IPD (85%) had urgency and frequency but were not incontinent; 66% of the patients with MSA and 16% of patients with IPD had a significant post-void residual volume. Of the men with MSA, 93% had erectile dysfunction and in 48% of them this complaint preceded the diagnosis of MSA. All 11 men with MSA who had a TURP were incontinent post-operatively. CONCLUSION: The urogenital criteria which favour a diagnosis of MSA are: (i) urinary symptoms preceding or presenting with parkinsonism; (ii) urinary incontinence and IPD; (iii) a significant post-void residual urine volume; (iv) erectile failure preceding or presenting with parkinsonism; and (v) worsening bladder control after urological surgery. Patients with parkinsonism and these features should be offered medical management rather than urological surgery.

Electromyography↗