Cognitive dysfunction in Parkinson's disease: from early symptoms to diagnosis

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects over six million people worldwide. It is classically characterized by the emergence of motor symptoms including bradykinesia/akinesia, rigidity, tremor, and postural instability. In the past decade, PD has increasingly been recognized as a mixed motor, non-motor and multiorgan disorder rather than a pure movement disorder. Cognitive impairment is a common non-motor complication of PD that is associated with significant disability in patients and caregiver burden. The thesis covers three aspects of cognitive dysfunction in PD through three studies. The first study, “Cognitive dysfunction in prodromal Parkinson’s disease: a qualitative review,” focuses on cognitive symptoms in prodromal PD. Today it is known that, by the time motor symptoms allow for clinical diagnosis, 40-60% of the dopaminergic neurons have already degenerated. The period of time in which neurodegeneration progresses in the absence of classical motor symptoms that allow a clinical diagnosis is termed the “prodromal phase of PD.” While other non-motor symptoms that represent possible prodromal symptoms of PD have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of the review was to summarize the current state of research on cognitive changes in prodromal PD. It shows that only a small number of longitudinal studies have been conducted that examine cognitive functions in individuals with a subsequent PD diagnosis. However, when considering data from at-risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores, were reduced. Prospective, longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal non-motor symptom complex that may precede motor manifestation of PD by years. Such information may help in updating the risk scores used for early identification of PD. The second study, “Verbal Memory Declines More in Female Patients with Parkinson’s Disease: the Importance of Gender-Corrected Normative Data,” concerns gender-specific profiles of cognitive function in patients with PD. So far, little data is available, the findings have been inconsistent, and possible disease-confounding factors have not been adequately considered. The LANDSCAPE study on cognition in PD enrolled 656 PD patients; raw values and age-, education-, and gender-corrected Z-scores were compared between genders. Motor symptoms, disease duration, levodopa equivalent daily dose, depression, and age and education for the raw value analysis were taken as covariates. The raw score analysis replicated the results of previous studies in that female PD patients were superior in terms of verbal memory, while men outperformed women in visuoconstruction and figural memory. In contrast, the gender-corrected Z-scores showed the men to be superior in verbal memory, while no difference was found for the visuospatial tests. It can be concluded that normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is greater in women than in men with PD. Future studies are needed to replicate these findings, to examine the progression of gender-specific cognitive decline in PD, and to define the different underlying mechanisms of this dysfunction. The third study, “Screening for Cognitive Impairment in Parkinson’s Disease: Improving the Diagnostic Utility of the MoCA through Subtest Weighting,” deals with cognitive screening in PD, which is highly relevant to clinical practice. The Montreal Cognitive Assessment (MoCA) is a screening test that is frequently used in PD to detect mild cognitive impairment (PD-MCI) and Parkinson’s disease dementia (PD-D). However, the subtests’ proportional representation in the MoCA total score does not seem reasonable. An empirically based alternative scoring system of the MoCA that is based on subtests´ individual sensitivity and specificity, and which aims to increase the instrument’s overall diagnostic accuracy, was developed and underwent preliminary evaluation. Diagnostic accuracy increased with the new MoCA scoring algorithm. In the first substudy, the sensitivity of detecting cognitive impairment increased from 62.5% to 92%, while specificity decreased only slightly from 77.7% to 73%; in the second substudy, sensitivity increased from 68.8% to 81.3%, while specificity remained stable at 75%. It can be concluded that the sensitivity of the MoCA can be enhanced substantially by an empirically based weighting procedure, and that the proposed scoring algorithm may better serve the MoCA’s purpose as a screening tool for the detection of cognitive dysfunction in PD patients than the original scoring. Further research with larger sample sizes is necessary to establish the efficacy of the alternate scoring system.