Prevalence of Submandibular Gland Synucleinopathy in Parkinson's Disease, Dementia with Lewy Bodies and other Lewy Body Disorders

Abstract

Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders.

Objective: To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders.

Methods: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA).

Results: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects.

Conclusions: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.

Keywords: Biopsy; biomarker; clinical trial; diagnosis; pathology; therapy.

Figure 1

Photomicrographs of sections stained immunohistochemically for phosphorylated α-synuclein. A) Low magnification of gland from a PD subject with immunoreactive fibers in the stroma around some large ducts. B) Low magnification of gland from a DLB subject with immunoreactive fibers at the periphery of a small artery in the stroma. C – E) Low, medium and high magnification of gland from an ILBD subject with immunoreactive fibers running within nerve fascicles in the stroma. F) High magnification of single immunoreactive nerve fibers amongst serous gland cells in a PD subject. G) High magnification of gland from a DLB subject with a single immunoreactive fiber in the stroma. H) High magnification of immunoperoxidase reaction product within the cytoplasm of serous gland cells in the submandibular gland of a subject with PD. This type of staining was seen in control subjects as well as in subjects with Lewy body disorders and is therefore considered diagnostically non-specific. I and J) High magnification of a nerve fascicle in the gland stroma of a DLB subject, stained with an immunofluorescent method for neurofilament (I, red) and phosphorylated α-synuclein (J, green) and viewed using a fluorescence microscope. K) Medium magnification of a nerve fascicle in the gland stroma of an ILBD subject, stained with an immunofluorescent method for neurofilament (red) and phosphorylated α-synuclein (green) and viewed with a confocal laser microscope. L) High magnification of a nerve fascicle in the gland stroma of an ILBD subject, stained with an immunofluorescent method for neurofilament (red) and phosphorylated α-synuclein (green) and viewed with a confocal laser microscope. Merged fibers are orange.