Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders

Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA.
Acta Neuropathologica (Impact Factor: 10.76). 12/2008; 117(2):169-74. DOI: 10.1007/s00401-008-0450-7
Source: PubMed


Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson's Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

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    • "Synucleins comprise a family of small proteins (14–17 kd) that were first identified in normal and neoplastic brain tissues (Fung et al., 2003; George, 2002). It is well established that ␣-synuclein is a key component of the Lewy body, a large globular protein complex that plays a critical role in the pathogenesis of Parkinson's disease (PD) and other dementias known as synucleinopathies (Beach et al., 2009; Bendor et al., 2013). The function of ␣-synuclein in the hematopoietic system is largely unknown. "
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    ABSTRACT: α-synuclein plays a crucial role in Parkinson's disease and dementias defined as synucleinopathies. α-synuclein is expressed in hematopoietic and immune cells, but its functions in hematopoiesis and immune responses are unknown. We utilized α-synuclein-/− (KO) mice to investigate its role in hematopoiesis and B cell lymphopoiesis. We demonstrated hematologic abnormalities including mild anemia, smaller platelets, lymphopenia but relatively normal early hematopoiesis in KO mice compared to wild-type (WT) as measured in hematopoietic stem cells and progenitors of the different cell lineages. However, the absolute number of B220+IgM+ B cells in bone marrow was reduced by 4-fold in KO mice (WT: 104 ± 23 × 105 vs. KO: 27 ± 5 × 105). B cells were also reduced in KO spleens associated with effacement of splenic and lymph node architecture. KO mice showed reduced total serum IgG but no abnormality in serum IgM was noted. When KO mice were challenged with a T cell-dependent antigen, production of antigen specific IgG1 and IgG2b was abolished, but antigen specific IgM was not different from WT mice. Our study shows hematologic abnormalities including anemia and smaller platelets, reduced B cell lymphopoiesis and defects in IgG production in the absence of α-synuclein. This is the first report to show an important role of α-synuclein late in hematopoiesis, B cell lymphopoiesis and adaptive immune response
    Immunobiology 11/2014; 219(11). DOI:10.1016/j.imbio.2014.07.014 · 3.04 Impact Factor
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    • "The presence of a-synuclein aggregates in the olfactory bulb, however, is densest in the bulbar anterior olfactory nucleus, which correspond to third-order neurons (Braak et al. 2003a; Del Tredici et al. 2002; Hubbard et al. 2007; Pearce et al. 1995; Sengoku et al. 2008; Ubeda-Banon et al. 2010a). Indeed, a-synuclein aggregates are particularly conspicuous along the different subdivisions of the anterior olfactory nucleus (Ubeda-Banon et al. 2010a), to the point that olfactory bulb biopsies have been proposed as a means to confirm diagnosis in PD subjects being assessed for surgical therapy (Beach et al. 2009). The fact that the densest labeling in the olfactory system occurs in the anterior olfactory nucleus cannot be exclusively explained from olfactory bulb afferent connections, but it is probably due to its multiple centripetal, centrifugal, commissural, associational, and non-olfactory connections. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigidity, resting tremor, and postural instability. Neuropathologically, intracellular aggregates of α-synuclein in Lewy bodies and Lewy neurites appear in particular brain areas according to a sequence of stages. Clinical diagnosis is usually established when motor symptoms are evident (corresponding to Braak stage III or later), years or even decades after onset of the disease. Research at early stages is therefore essential to understand the etiology of PD and improve treatment. Although classically considered as a motor disease, non-motor symptoms have recently gained interest. Olfactory deficits are among the earliest non-motor features of PD. Interestingly, α-synuclein deposits are present in the olfactory bulb and anterior olfactory nucleus at Braak stage I. Several lines of evidence have led to proposals that PD pathology spreads by a prion-like mechanism via the olfactory and vagal systems to the substantia nigra. In this context, current data on the temporal appearance of α-synuclein aggregates in the olfactory system of both humans and transgenic mice are of particular relevance. In addition to the proposed retrograde nigral involvement via brainstem nuclei, olfactory pathways could potentially reach the substantia nigra, and the possibility of centrifugal progression warrants investigation. This review analyzes the involvement of α-synuclein in different elements of the olfactory system, in both humans and transgenic models, from the hodological perspective of possible anterograde and/or retrograde progression of this proteinopathy within the olfactory system and beyond-to the substantia nigra and the remainder of the central and peripheral nervous systems.
    Brain Structure and Function 10/2013; 219(5). DOI:10.1007/s00429-013-0651-2 · 5.62 Impact Factor
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    • "Firstly, from a pathophysiological perspective, they may be caused by different mechanisms. hyposmia in PD was associated with alpha-synuclein accumulation in central olfactory system, especially the olfactory bulb [12,13]. Whereas, SN hyperechogenicity may reflect increased SN iron content in PD, this was demonstrated in animal models and postmortem human brains [14,15]. "
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    ABSTRACT: Objectives Both hyposmia and substania nigra (SN) hyperechogenicity on trascranial sonography (TCS) were risk markers for idiopathic Parkinson’s disease (PD), which was beneficial to the differential diagnosis of the disease. However, each of their single diagnostic value is often limited. The purpose of present study was to explore whether the combination of olfactory test and TCS of SN could enhance the differential diagnostic power in Chinese patients with PD. Methods Thirty-seven patients with PD and twenty-six patients with essential tremor (ET) were evaluated on 16-item odor identification test from extended version of sniffin’ sticks and TCS of SN. The frequency of hyposmia and SN hyperechogenicity in each group was compared. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two clinical biomarkers were analyzed. Results The frequency of hyposmia in patients with PD was significantly higher than in patients with ET (62.2% VS. 3.8%, P = 0.000). The frequency of SN hyperechogenicity in patients with PD was significantly higher than in ET subjects (48.6% VS. 15.4%, P = 0.006). The combination of hyposmia and SN hyperechogenicity (if either one or both present) discriminated patients with PD from ET with a sensitivity of 78.4% and 29.7%, specificity of 80.8% and 100%, PPV of 85.3% and 100%, and NPV of 72.4% and 50.0%, respectively. Conclusions Our preliminary data suggested that the combination of hyposmia and SN hyperechogenicity could improve the diagnostic potential for discriminating Chinese patients with PD from ET.
    Translational Neurodegeneration 12/2012; 1(1):25. DOI:10.1186/2047-9158-1-25
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