Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Abstract

Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson’s disease (PD). However mounting data from genetic-PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. Here we review the literature of genetic-PD autopsies from cases with molecularly-confirmed PD or parkinsonism and summarize main findings on SNCA (n=25), Parkin (n=20, 17 bi-allelic and 3 heterozygotes), PINK1 (n=5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n=1), LRRK2 (n=55), GBA (n=10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n= 8 patients, two with PD), MPAN (n=2), FBXO7, RAB39B and ATXN2 (SCA2), as well as on 22q deletion syndrome (n=3). Findings from autopsies of heterozygous mutation carriers of genes which are traditionally considered recessively-inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (e.g., MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (e.g., LRRK2-PD or Parkin-PD). Therefore, we may conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number of reported genetic-PD autopsies remains small and there are limited genotype-clinical-pathological-phenotype studies. Therefore, larger series of autopsies from genetic-PD patients are required.

α‐Synuclein real‐time quaking‐induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism

“…Because there was only 1 genetic case in our cohort, we could only speculate that the CSF α-syn RT-QuIC test might not be suitable for detecting all patients with a genetic form of PD, as autopsy reports of genetic (including PARK2) PD cases have shown that Lewy bodies may be either present or absent. 17 Unexpected positive test results were found in 5 of 79 cases. The 1 PSP patient with a positive test result was a patient who, at disease onset, had clinical MSA-like features with prominent autonomic features (unusual for PSP), but at follow-up had clinical features that were more PSP-like (including supranuclear gaze palsy).…”

Are genetic and idiopathic forms of Parkinson's disease the same disease?

“… Atypical park: atypical parkinsonism; AD, autosomal dominant; AR, autosomal recessive; X‐linked R/D, X‐linked recessive/ dominant; *, in SNCA duplications; α, (Marras et al, ); #, Adapted (Vincenzo Bonifati, ); ß: (Schneider and Alcalay, ). …”

“…As such, neuropathological criteria for definite diagnosis of PD have included the loss of dopaminergic neurons in the SNc and the presence of Lewy pathology (Daniel and Lees, 1993) (Gelb, Oliver, and Gilman, 1999) (Dickson et al, 2009). Neuropathological studies in genetic forms of PD challenge this concept: SNCA-related PD cases have presented tau inclusions, TDP-43 inclusions in neurites and cell bodies in the temporal cortex (Markopoulou et al, 2008) or MSA-like features (Pasanen et al, 2014); G2019S-related PD cases have been found to have no Lewy pathology (Poulopoulos, Levy, and Alcalay, 2012);and PRKN is associated with none or little asynuclein deposition (Schneider and Alcalay, 2017).…”

Leucine rich repeat kinase 2: a paradigm for pleiotropy

“…These criteria are matched by the majority of people with Parkinson's disease carrying mutations in LRRK2 . A subset, however, and perhaps as high as 1 in 10, diverge from this canonical pathology (Schneider & Alcalay, ). This was noted in one of the original papers reporting the identification of mutations in LRRK2 , describing pleiomorphic pathology in a kindred from western Nebraska.…”