Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

Abstract

Background Patients with dementia with Lewy bodies reveal a variable pathology including alpha‐synuclein, amyloid‐beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha‐synuclein. Objective Whether GBA1 mutations are associated with a CSF alpha‐synuclein profile in dementia with Lewy bodies. Methods Screening of the GBA1 gene and single‐nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha‐synuclein, amyloid‐beta1‐42, total‐Tau, phospho‐Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross‐sectionally. Results Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha‐synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype. Conclusion Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha‐synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha‐synuclein–lowering compounds. © 2019 International Parkinson and Movement Disorder Society

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

“…The finding that disease risk and clinical characteristics in PD and DLB seem dependent on GBA1 mutation severity are consistent with previous reports . We now show for both disease entities that CSF biomarker profiles of total alpha‐synuclein also seem dependent on mutation severity.…”

“…In the era when disease‐modifying treatment options such as alpha‐synuclein–lowering compounds are tested in clinical trials, patient stratification according to alpha‐synuclein–specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite to introduce patients to specific therapies. We could previously show that PD GBA and DLB GBA show reduced CSF levels of total alpha‐synuclein compared to the wildtype condition and to healthy control individuals . Importantly, in DLB GBA , this phenomenon was dependent on mutation severity.…”

“…We could previously show that PD GBA and DLB GBA show reduced CSF levels of total alpha-synuclein compared to the wildtype condition and to healthy control individuals. 6,8 Importantly, in DLB GBA , this phenomenon was dependent on mutation severity. However, data on CSF alpha-synuclein profiles in PD GBA stratified by mutation severity are missing.…”

“…Clinically, PD and DLB patients carrying a GBA1 mutation (PD GBA , DLB GBA ) present with an earlier age of onset, suffer more frequently from nonmotor symptoms, specifically cognitive decline, and show a more rapid disease progression when compared with patients without the GBA mutation (PD GBA_wildtype , DLB GBA_wildtype ) . Of note, the severity of the clinical phenotype and/or progression have been associated with mutation severity in both entities …”

“…3,4 Of note, the severity of the clinical phenotype and/or progression have been associated with mutation severity in both entities. 5,6 Mechanistically, the encoded enzyme glucocerebrosidase (GCase) and alpha-synuclein form a bidirectional pathogenic loop. The functional loss of GCase as a result of GBA1 mutations compromises lysosomal alpha-synuclein degradation causing alpha-synuclein accumulation while alpha-synuclein itself inhibits lysosomal activity of GCase.…”