Multiple sclerosis in LRRK2 G2019S Parkinson's disease and isolated nigral degeneration in a homozygous variant carrier

Abstract

Background: LRRK2 variants have been associated with immune dysregulation as well as immune-related disorders such as IBD. A possible relationship between multiple sclerosis (MS) and LRRK2 PD has also been suggested. Further, neuropathologic studies of homozygous LRRK2 G2019S carriers with Parkinson's disease (PD) are rare, and there are no systematic reports of clinical features in those cases.

Methods: We investigated the co-occurrence of PD and MS in our research cohort and report on two cases of MS in LRRK2 PD as well as neuropathological findings for one.

Results: MS preceded PD in 1.4% (2/138) of participants with LRRK2 G2019S variants, and in none (0/638) with idiopathic PD (p = 0.03). One case with MS and PD was a LRRK2 G2019S homozygous carrier, and neuropathology showed evidence of substantia nigra pars compacta degeneration and pallor without Lewy deposition, as well as multiple white matter lesions consistent with MS-related demyelination.

Discussion: The increased prevalence of MS in LRRK2 PD further supports an important role for immune function for LRRK2 PD. This co-occurrence, while rare, suggests that MS may be an expression of the LRRK2 G2019S variant that includes both MS and PD, with MS predating features diagnostic of PD. The neuropathology suggests that the MS-related effects occurred independent of synuclein deposition. Importantly, and in addition, the neuropathological results not only support the MS diagnosis, but provide further evidence that Lewy body pathology may be absent even in homozygote LRRK2 carriers.

Keywords: LRRK2; Parkinson’s disease; Parkinson’s genes; autoimmune diseases; genetic; genetic risk; immunology & inflammation; multiple sclerosis.

Figure 1

Neuropathological and neuroimaging evaluation demonstrating multiple sclerosis and brainstem degeneration in the absence of nigral Lewy bodies. (A) Gross coronal sections showing scattered white matter plaques (white arrows). (B) Luxol fast blue counterstained hematoxyoin & eosin stained (LH&E) section from the cervical spinal cord showing myelin pallor in the lateral funiculus. (C) Immunohistochemistry (IHC) using antisera targeting neurofilament shows intact axons consistent with a demyelinating process. (D) b-CIT SPECT revealed marked, symmetrically reduced uptake indicating significant loss of striatal dopamine neuronal innervation. (E) Gross hemisection of the midbrain demonstrating marked pallor in the substantia nigra. (F) High power (20x) photomicrograph of an LH&E-stained section through the midbrain showing marked loss of pigmented dopaminergic neurons and reactive gliosis. Immunohistochemistry to α-synuclein shows mild Lewy pathology (white arrowheads) in the olfactory bulb (G), negative staining in the substantia nigra (H), cingulate gyrus (I), amygdala (J), frontal cortex (K), hippocampus (L), and positive staining in the medulla, including the dorsal motor nucleus of the vagus (DMX; M), nucleus gigantocellularis (N), and medial lemniscus (O).