Predicting cognitive decline in Parkinson's disease: can we ask the genes?
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ABSTRACT:
SUBMITTER: De Marchi F
PROVIDER: S-EPMC4209831 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Predicting cognitive decline in Parkinson's disease: can we ask the genes?
De Marchi Fabiola F Carecchio Miryam M Cantello Roberto R Comi Cristoforo C
Frontiers in neurology 20141027
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Project description:BackgroundCognitive impairment is a common symptom of Parkinson's disease (PD) that increases in risk and severity as the disease progresses. An accurate prediction of the risk of progression from the mild cognitive impairment (MCI) stage to the dementia (PDD) stage is an unmet clinical need.MethodsWe investigated the use of a supervised learning algorithm called the support vector machine (SVM) to retrospectively stratify patients on the basis of brain fluorodeoxyglucose-PET (FDG-PET) scans. Of 43 patients with PD-MCI according to the baseline scan, 23 progressed to PDD within a 5-year period, whereas 20 maintained stable MCI. The baseline scans were used to train a model, which separated patients identified as PDD converters versus those with stable MCI with 95% sensitivity and 91% specificity.ResultsIn an independent validation data set of 19 patients, the AUC was 0.73, with 67% sensitivity and 80% specificity. The SVM model was topographically characterized by hypometabolism in the temporal and parietal lobes and hypermetabolism in the anterior cingulum and putamen and the insular, mesiotemporal, and postcentral gyri. The performance of the SVM model was further tested on 2 additional data sets, which confirmed that the model was also sensitive to later-stage PDD (17 of 19 patients; 89% sensitivity) and dementia with Lewy bodies (DLB) (16 of 17 patients; 94% sensitivity), but not to normal cognition PD (2 of 17 patients). Finally, anti-PD medication status did not change the SVM classification of the other set of 10 patients with PD who were scanned twice, ON and OFF medication.ConclusionsThese results potentially indicate that the proposed FDG-PET-based SVM classifier has utility for providing an accurate prognosis of dementia development in patients with PD-MCI.
| S-EPMC9566889 | biostudies-literature
Project description:ObjectivesCognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val158 Met genotype and DRD2 C957 T genotype) affect the development of cognitive deficits in PD.Materials and methodsOne hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome.ResultsBoth genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT 158 Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P = .023), the DRD2 957 T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P < .001). The poorer cognitive performance in DRD2 957 T/T carriers with PD occurred mainly in episodic memory and attention.ConclusionsThe results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas.
| S-EPMC5763317 | biostudies-literature
Project description:BackgroundCognitive impairment is common in Parkinson's disease (PD), with 80% cumulatively developing dementia (PDD).ObjectiveWe sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD.MethodsParticipants with newly diagnosed PD (n = 211) and age-matched controls (n = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD.ResultsAt 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p < 0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p < 0.001) compared to control-generated cut-offs (AUC = 0.76-0.84,p < 0.001) and PD-MCI (AUC = 0.64-0.81, p < 0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p < 0.001).ConclusionVerbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification.
| S-EPMC8461722 | biostudies-literature
Project description:Cognitive decline is common with the progression of Parkinson's disease (PD). Different candidate biomarkers are currently studied for the risk of dementia in PD. Several studies have shown that quantitative EEG (QEEG) is a promising predictor of PD-related cognitive decline. In this paper we briefly outline the basics of QEEG analysis and analyze the recent publications addressing the predictive value of QEEG in the context of cognitive decline in PD. The MEDLINE database was searched for relevant publications from January 01, 2005, to March 02, 2015. Twenty-four studies reported QEEG findings in various cognitive states in PD. Spectral and connectivity markers of QEEG could help to discriminate between PD patients with different level of cognitive decline. QEEG variables correlate with tools for cognitive assessment over time and are associated with significant hazard ratios to predict PD-related dementia. QEEG analysis shows high test-retest reliability and avoids learning effects associated with some neuropsychological testing; it is noninvasive and relatively easy to repeat.
| S-EPMC4842380 | biostudies-literature
Project description:The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ?4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ? 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ?4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.
| S-EPMC3323737 | biostudies-literature
Project description:We evaluated 128 GBA and 432 nonGBA Parkinson's disease (PD) subjects available from Parkinson's Progression Markers Initiative. Baseline clinical features and dopaminergic activity were assessed, together with clinical follow-up (6.87 ± 3.2 years). Survival analyses assessed the independent and interactive effects of sex and GBA1 mutations on cognitive decline. At baseline, GBA-PD males showed severe motor impairment, sleep disorders and memory deficits. Despite milder motor deficit, compared to GBA-PD males, GBA-PD females showed greater dopaminergic denervation, suggesting the effect of neural reserve. In longitudinal assessment, GBA-PD males showed greater MoCA rate of change per year and greater risk of cognitive impairment than GBA-PD females and nonGBA-PD. In GBA-PD males, both late age at onset and "severe/mild" GBA variants were associated with increased risk of cognitive impairment. Male sex and GBA1 carrier status have an additive value in increasing the risk of cognitive decline in PD. The effect of sex on GBA1-related pathology warrants further examination to address future trials design and patients' selection.
| S-EPMC11880540 | biostudies-literature
Project description:BackgroundCognitive impairment (CI) is one of the most feared and debilitating complications of PD. No therapy has been shown to slow or prevent CI in PD.ObjectiveTo determine associations between modifiable comorbidities, including cardiovascular disease risk factors, mood disorders, and sleep characteristics, and rate of cognitive decline in Parkinson's disease (PD).MethodsData from the Parkinson's Progression Markers Initiative (PPMI) cohort was queried for baseline cardiovascular disease risk factors, mood disorders, and sleep characteristics. Linear mixed- effects models (LME) were used to examine the association between baseline factors and change in cognition, evaluated by the Montreal Cognitive Assessment (MoCA) over time. Baseline comorbidities found to affect MoCA decline were assessed for an association with focal cognitive domains using LME.ResultsHigher Body Mass Index (BMI) (β = -0.009, P = 0.039), State Trait Anxiety Inventory (STAI) (β = -0.005, P < 0.001), Geriatric Depression Scale (GDS) (β = -0.034, P < 0.001), Epworth Sleepiness Scale (ESS) (β = -0.017, P = 0.003), and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) (β = -0.037, P < 0.001) were associated with faster rates of MoCA decline. Using established cut-offs for clinically significant symptoms, being overweight, or the presence of depression, excessive day time sleepiness (EDS), and possible REM sleep behavior disorder (pRBD), were all associated with faster rate of cognitive decline.ConclusionSeveral modifiable baseline comorbidities are associated with faster rate of CI over time in patients with PD. These associations identify potential opportunities for early intervention that could influence CI in PD.
| S-EPMC7853194 | biostudies-literature
Project description:BackgroundCognitive deficits are associated with poor quality of life and increased risk of development of dementia in patients with Parkinson's disease (PD) psychosis. The trajectory of cognitive decline in PD psychosis remains however unclear.ObjectiveWe examined this using data from the Parkinson's Progression Markers Initiative study.MethodsWe analysed data from patients with drug-naïve PD (n=676) and healthy controls (HC, n=187) over 5 years, and examined all cognitive measures assessed at each time point. We classified patients with PD into those who developed psychosis over the course of the study (PDP) and those without psychosis throughout (PDnP) using the Movement Disorders Society Unified Parkinson's Disease Rating Scale part I hallucinations/psychosis item. We used linear mixed-effect models with restricted maximum likelihood. Age, sex, ethnicity, education and neuropsychiatric and PD-specific symptoms were entered as covariates of interest.FindingsThere were no baseline cognitive differences between PD patient groups. There were differences in cognitive performance between PD and HC across the majority of the assessments.Patients with PDP exhibited greater cognitive decline over 5 years compared with PDnP across most domains even after controlling for sociodemographics, depression, sleepiness, rapid eye movement sleep behaviour disorder and motor symptom severity (immediate recall, b=-0.288, p=0.003; delayed recall, b=-0.146, p=0.003; global cognition, Montreal Cognitive Assessment, b=-0.206, p<0.001; visuospatial, b=-0.178, p=0.012; semantic fluency, b=-0.704, p=0.002; processing speed, b=-0.337, p=0.029).ConclusionsPatients with PD psychosis exhibited decline in semantic aspects of language, processing speed, global cognition, visuospatial abilities and memory, regardless of sociodemographic characteristics, neuropsychiatric and motor symptoms. These cognitive domains, particularly semantic aspects of language may therefore play an important role in PD psychosis and warrant further investigation.Trial registration numberNCT01141023.
| S-EPMC11268075 | biostudies-literature
Project description:Clinical and biochemical diversity of Parkinson's disease (PD) presents a major challenge for accurate diagnosis and prediction of its progression. We propose, develop and optimize PD clinical scores as efficient integrated progression biomarkers for prediction of the likely rate of cognitive decline in PD patients. We considered 269 drug-naïve participants from the Parkinson's Progression Marker Initiative database, diagnosed with idiopathic PD and observed between 4 and 6 years. Nineteen baseline clinical and pathological measures were systematically considered. Relative variable importance and logistic regressions were used to optimize combinations of significant baseline measures as integrated biomarkers. Parkinson's disease cognitive decline scores were designed as new clinical biomarkers using optimally categorized baseline measures. Specificities and sensitivities of the biomarkers reached ~93% for prediction of severe rate of cognitive decline (with more than 5 points decline in 4 years on the Montreal Cognitive Assessment scale), and up to ~73% for mild-to-moderate decline (between 1 and 5 points decline). The developed biomarkers and clinical scores could resolve the long-standing clinical problem about reliable prediction of PD progression into cognitive deterioration. The outcomes also provide insights into the contributions of individual clinical and pathological measures to PD progression, and will assist with better-targeted treatment regiments, stratification of clinical trial and their evaluation.
| S-EPMC6877592 | biostudies-literature
Project description:ObjectiveTo evaluate the association between baseline olfaction and both cross-sectional and longitudinal cognitive assessments, motor symptoms, non-motor symptoms (NMS), and CSF biomarkers in early Parkinson's disease (PD).MethodsParkinson's Progression Marker's Initiative (PPMI) participants underwent baseline olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT). Serial assessments included measures of motor symptoms, NMS, neuropsychological assessment, and CSF biomarkers. Up to three years follow-up data were included.ResultsAt baseline, worse olfaction (lowest tertile) was associated with more severe NMS, including anxiety and autonomic symptoms. Those in the lowest olfactory tertile were more likely to report cognitive impairment (37.4%) compared to those in the middle (24.4%) and highest olfactory tertiles (14.2%, p < 0.001). Aβ1-42 was significantly lower, and tau/Aβ1-42 ratio was higher in those with worse olfaction. In longitudinal analyses, lower UPSIT score was associated with greater decline in MoCA score (β = 0.02 [0.01, 0.03], p = 0.001) over time, as were composite measures of UPSIT score and either Aβ1-42 or tau/Aβ1-42 ratio. In a Cox proportional hazards model, a composite measure of olfaction and Aβ1-42 was a significant predictor of conversion from normal cognition to mild cognitive impairment (MCI; i.e., MoCA < 26), with subjects most impaired on both measures being 87% more likely to develop incident MCI (HR = 1.87 [1.16, 3.01], p = 0.01).ConclusionsWorse baseline olfaction is associated with long-term cognitive decline. The addition of AD CSF biomarkers to olfactory testing may increase the likelihood of identifying those at highest risk for cognitive decline and progression to MCI.
| S-EPMC4825674 | biostudies-literature