Synucleinopathy with features of both multiple system atrophy and dementia with Lewy bodies

Alpha-synuclein is a main component of neuronal inclusions in Parkinson’s disease, dementia with Lewy bodies (DLB) and glial and neuronal inclusions in multiple system atrophy (MSA) – as a group often referred to as alpha-synucleinopathies [1,2]. Dementia with Lewy bodies is the second most frequent neurodegenerative dementing disorder in the elderly after Alzheimer’s disease. Clinically, it is associated with fluctuating cognition and hallucinations in association with neurological features of Parkinsonism. DLB is neuropathologically characterized by the presence of Lewy bodies (LBs) in the brain [3]. Classically, LBs appear as one or more intraneuronal eosinophilic spherical structures with a dense core. They are often surrounded by a halo, although in the neocortex they usually lack the halo and may be inconspicuous in routine staining. Multiple system atrophy is a sporadic neurodegenerative disease clinically characterized by varying degrees of Parkinsonism, cerebellar ataxia and/or features of autonomic failure. The term MSA was coined to unify three separate entities: striatonigral degeneration, olivopontocerebellar atrophy and the Shy–Drager syndrome, which may overlap clinically and pathologically [4]. However, it was not until 1989, when Papp and Lantos described filamentous inclusions in the cytoplasm of oligodendroglial cells in the brains of patients with MSA, irrespective of clinical symptoms, that the existence of MSA as a clinicopathological entity was confirmed [5]. Glial cytoplasmic inclusions (GCIs), also called Papp–Lantos bodies, were more recently shown also to be composed mainly of alpha-synuclein [1,6]. Similar inclusions were later identified in neuronal cytoplasm (neuronal cytoplasmic inclusions, or NCIs) and in the nuclei of neurones and oligodendrocytes [7,8]. The clinical phenotype depends on the neuronal systems predominantly involved; hence, the two clinical presentations are now designated MSAcerebellar type and MSA-Parkinsonism. We report here an archival case of a 51-year-old woman with progressive cognitive deficits, psychotic symptoms (hallucinations) and muscle rigidity, who died of unrelated gastric haemorrhage a year after the onset of neurological and psychiatric signs. According to the archival files, the patient presented on admission with delirium superposed on progressive dementia. Neuroleptic sensitivity reaction (extrapyramidal signs) occurred during the course of the disease. Owing to the lack of detailed clinical data, thorough analysis of the clinical phenotype of this patient could not be performed in this retrospective study. Brain autopsy was performed after 14 days of fixation in 4% formaldehyde. Recently, the archival paraffin blocks were re-examined. Fivemicrometre-thick sections were obtained from each tissue block for routine stainings, conventional immunohistochemistry and double immunofluorescent labelling. Immunohistochemistry was performed using a panel of antibodies (Table 1) according to the producers’ protocols. As a secondary system we used the ChemMateTM detection kit Dako, Glostrup, Denmark. For immunofluorescent labelling and multichannel confocal microscopy we used mouse anti-microtubuleassociated protein (MAP)-2 monoclonal antibody (Chemicon International, Inc. Temecula, CA, USA, dilution 1:250) and rat anti-a-synuclein monoclonal antibody (Alexis Bichemicals, Lausen, Switzerland, dilution 1:100). The fluorescent-labelled secondary antibody for the antia-synuclein antibody was Alexa Fluor 488 rabbit anti-rat IgG (Molecular Probes, Eugene, USA, 1:200) and for antiMAP-2 Alexa Fluor 546 goat anti-mouse IgG (Molecular Probes, 1:200). To visualize cell nuclei, Sytox orange stain was used (Dako, Glostrup, Denmark). Immunofluorescence labelling was evaluated using a Zeiss LSM 510 laser scanning confocal microscope. Material for electron microscopy was retrieved from formalin-fixed, paraffin-embedded sections and reprocessed for electron microscopy. On gross neuropathological examination, moderate and diffuse brain atrophy was observed, along with slight depigmentation of the substantia nigra. Microscopic examin-