Pathological description of a non-motor variant of multiple system atrophy

Neurology Service, Hospital Clinic de Barcelona, C/Villarroel 170, Barcelona 08036, Spain.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 01/2009; 79(12):1399-400. DOI: 10.1136/jnnp.2008.145276
Source: PubMed


Multiple system atrophy (MSA) is a neurodegenerative disorder that usually presents clinically as a combination of parkinsonism, cerebellar syndrome and autonomic failure. Patients with MSA can present other clinical features, such as inspiratory stridor and rapid eye movement (REM) sleep behaviour disorder (RBD). We report a patient with pathologically confirmed MSA who presented with a longstanding history of stridor, RBD and autonomic disturbances but did not develop overt parkinsonism or cerebellar signs. This case illustrates that MSA may present clinically without its cardinal motor symptoms, and that stridor and RBD may be clues to recognise the disease in a patient with autonomic failure.

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    • "RBD associated with neurodegenerative disease was first appreciated over 15 years ago [13], and because RBD often precedes the onset of a slowly evolving neurodegenerative syndrome by years or decades [3,5,10,13–28], international attention has turned to view iRBD as a potential early clinical manifestation and biomarker of sorts of neurodegeneration rather than a curious parasomnia. Other features on PSG also can suggest an evolving neurodegenerative disorder such as laryngeal stridor and slowing of electroencephalogram activity [29] [30] [31]. If iRBD is a harbinger of parkinsonism, cognitive impairment, autonomic dysfunction, or some combination of these, at least in some individuals, one would hope that an intervention could be commenced and potentially delay the onset of these disabling features or prevent them from occurring altogether. "
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    ABSTRACT: Objective: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. Results: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. Conclusions: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.
    Sleep Medicine 03/2013; 14(8). DOI:10.1016/j.sleep.2012.10.015 · 3.15 Impact Factor
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    • "A host of environmental, genetic, and immune cues have been associated with the onset of this disease [1]. Clinical symptoms of PD include tremor, bradykinesia, rigidity, and postural instability [2,3]. Pathologically, it is characterized by gliosis and progressive degeneration of the dopaminergic neurons associated with the presence of intracytoplasmic inclusions (Lewy bodies) in the substantia nigra pars compacta (SNc) [2,3]. "
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    ABSTRACT: Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood. The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model. Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment. JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis. These pro-apoptosis effect can be diminished by curcumin. Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP. Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.
    Translational Neurodegeneration 08/2012; 1(1):16. DOI:10.1186/2047-9158-1-16
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    • "Clinicopathological studies have linked orthostatic hypotension with degeneration of preganglionic sympathetic neurons in the intermediolateral columns (IML) of the spinal cord (Oppenheimer, 1980; Wenning et al., 1997), with failure of supraspinal cardiovascular control due to degeneration of catecholaminergic neurons in the ventrolateral medulla and locus coeruleus as well as preganglionic cholinergic neurons of nucleus ambiguus (NAmb) (Benarroch et al., 2002, 2006; Benarroch, 2003). Additional non-motor features of MSA including REM sleep behaviour disorder, erectile dysfunction and bladder hyperactivity appear to be related to loss of neurons in pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT) (Schmeichel et al., 2008; Gaig et al., 2008; Salas et al., 2008; Koyama et al., 1999). Anal and urethral sphincter failure in MSA has been associated with loss of neurons in Onuf's nucleus of the spinal cord (Mannen, 2000; Yamamoto et al., 2005). "
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    ABSTRACT: Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs). Using proteolipid protein (PLP)-alpha-synuclein (alpha SYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like alpha SYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-alpha SYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with alpha SYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like alpha SYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of alpha SYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-alpha SYN transgenic mouse model as a testbed for the study of oligodendroglial alpha SYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.
    Experimental Neurology 08/2010; 224(2):459-64. DOI:10.1016/j.expneurol.2010.05.008 · 4.70 Impact Factor
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