Thomas F Tropea1, Sharon X Xie2, Jacqueline Rick1, Lana M Chahine1, Nabila Dahodwala1, Jimit Doshi3, Christos Davatzikos3, Leslie M Shaw4, Vivianna Van Deerlin4, John Q Trojanowski4,5, Daniel Weintraub6,7, Alice S Chen-Plotkin1. 1. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3. Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 5. Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 6. Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 7. Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND: People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's disease patients. METHODS: We performed a prospective cohort study of 100 PD patients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline. RESULTS: In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P < 0.05). The APOE genotype effect was not specific to any Mattis Dementia Rating Scale-2 domain. CONCLUSIONS: Our results confirm the importance of Alzheimer's disease biomarkers as risk factors for cognitive decline in established Parkinson's disease.
BACKGROUND:People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's diseasepatients. METHODS: We performed a prospective cohort study of 100 PDpatients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline. RESULTS: In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P < 0.05). The APOE genotype effect was not specific to any Mattis Dementia Rating Scale-2 domain. CONCLUSIONS: Our results confirm the importance of Alzheimer's disease biomarkers as risk factors for cognitive decline in established Parkinson's disease.
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