Combined detrimental effect of male sex and GBA1 variants on cognitive decline in Parkinson’s Disease
Abstract Background and Objective Heterozygous variants in the glucocerebrosidase gene (GBA1) are the major genetic risk factor for Parkinson’s Disease (PD). GBA-PD has been associated with worse progression and higher risk of cognitive decline. Here we took advantage of the Parkinson’s Progression Markers Initiative (PPMI) to investigate whether sex could interact withGBA1carrier status in determining the clinical phenotype, with a special focus on cognitive decline.Methods We evaluated 118 PD subjects carryingGBA1variants (GBA-PD) and 450 with wild-type alleles (nonGBA-PD) included in the PPMI. Dopaminergic activity was assessed in a subset of 248 subjects (65%) with available123I-FP-CIT SPECT scans. Clinical features and dopaminergic activity were investigated in GBA-PD vs. nonGBA-PD groups, upon stratification by sex. PD subjects were followed for up to 6.5Dyears (median 6Dyears). Cox regression was used to model the hazard ratio (HR) of (1)GBA1genotype, (2) sex, (3) gene-by-sex interaction on cognitive decline at follow-up.Results Regardless of genotype, men suffering from PD exhibited higher motor disability while women showed more autonomic dysfunction. At baseline, GBA-PD showed more severe motor and non-motor features, and reduced dopamine uptake in the bilateral ventral putamen compared to nonGBA-PD. Within the GBA-PD group, males had higher occurrence of REM sleep behavior disorder and memory deficits. Of note, GBA-PD females showed a greater striatal dopaminergic deficit compared to males, despite presenting similar motor impairment. In longitudinal assessment, Cox Regression revealed that male sex (HR = 1.7),GBA1carrier status (HR =1.6) and, most importantly, GBA-by-male sex interaction (HR = 2.3) were significantly associated with a steeper cognitive decline. Upon stratification forGBA1variant class, both “severe” and “mild” variants were associated with increased risk of cognitive decline, again more relevant in males (HR = 2.3).Discussion We show, for the first time, that male sex andGBA1carrier status have an additive value in increasing the risk of cognitive decline in PD, despite the heightened dopaminergic vulnerability observed in GBA-PD females. The effect of sex onGBA1-related pathology warrants further examination and should be considered in future trials design and patients’ selection..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 05. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Caminiti, Silvia Paola [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.04.02.24305191 |
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| PPN (Katalog-ID): |
XBI043153445 |
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| 520 | |a Abstract Background and Objective Heterozygous variants in the glucocerebrosidase gene (GBA1) are the major genetic risk factor for Parkinson’s Disease (PD). GBA-PD has been associated with worse progression and higher risk of cognitive decline. Here we took advantage of the Parkinson’s Progression Markers Initiative (PPMI) to investigate whether sex could interact withGBA1carrier status in determining the clinical phenotype, with a special focus on cognitive decline.Methods We evaluated 118 PD subjects carryingGBA1variants (GBA-PD) and 450 with wild-type alleles (nonGBA-PD) included in the PPMI. Dopaminergic activity was assessed in a subset of 248 subjects (65%) with available123I-FP-CIT SPECT scans. Clinical features and dopaminergic activity were investigated in GBA-PD vs. nonGBA-PD groups, upon stratification by sex. PD subjects were followed for up to 6.5Dyears (median 6Dyears). Cox regression was used to model the hazard ratio (HR) of (1)GBA1genotype, (2) sex, (3) gene-by-sex interaction on cognitive decline at follow-up.Results Regardless of genotype, men suffering from PD exhibited higher motor disability while women showed more autonomic dysfunction. At baseline, GBA-PD showed more severe motor and non-motor features, and reduced dopamine uptake in the bilateral ventral putamen compared to nonGBA-PD. Within the GBA-PD group, males had higher occurrence of REM sleep behavior disorder and memory deficits. Of note, GBA-PD females showed a greater striatal dopaminergic deficit compared to males, despite presenting similar motor impairment. In longitudinal assessment, Cox Regression revealed that male sex (HR = 1.7),GBA1carrier status (HR =1.6) and, most importantly, GBA-by-male sex interaction (HR = 2.3) were significantly associated with a steeper cognitive decline. Upon stratification forGBA1variant class, both “severe” and “mild” variants were associated with increased risk of cognitive decline, again more relevant in males (HR = 2.3).Discussion We show, for the first time, that male sex andGBA1carrier status have an additive value in increasing the risk of cognitive decline in PD, despite the heightened dopaminergic vulnerability observed in GBA-PD females. The effect of sex onGBA1-related pathology warrants further examination and should be considered in future trials design and patients’ selection. | ||
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| 700 | 1 | |a Avenali, Micol |e verfasserin |4 aut | |
| 700 | 1 | |a Galli, Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Malito, Rachele |e verfasserin |4 aut | |
| 700 | 1 | |a Cuconato, Giada |e verfasserin |4 aut | |
| 700 | 1 | |a Pilotto, Andrea |e verfasserin |4 aut | |
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| 700 | 1 | |a Perani, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Tassorelli, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Valente, Enza Maria |e verfasserin |4 aut | |
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