Cognition and Other Non-Motor Symptoms in an At-Risk Cohort for Parkinson’s Disease Defined by REM-Sleep Behavior Disorder and Hyposmia

INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disorder with increasing prevalence. It is mostly diagnosed when more than 60% of the dopaminergic neurons are degenerated and first motor manifestations, such as tremor, rigidity, and slowness of movement, appear [1, 2]. The period between the onset of neuronal degeneration, where symptoms and signs are present, but yet insufficient to define the disease, and the clinical diagnosis is called the prodromal or pre-motor phase and can start up to 20 years before the onset of motor parkinsonism [3, 4]. Given that diagnosing PD means identifying an already advanced neurodegeneration, it is essential to focus on its early detection, e.g. by defining patterns of cognitive and other non-motor symptoms.

Research criteria for prodromal PD (P-PD) were proposed by the Movement Disorder Society (MDS) [5, 6]. Their findings suggest that polysomnographically proven REM-sleep behavior disorder (RBD), abnormal dopaminergic brain imaging (PET/SPECT), subthreshold motor parkinsonism and olfactory dysfunction are the prodromal markers with the highest likelihood to predict α-synucleinopathies, such as PD. Global cognitive deficit was only later added as a criterion for prodromal PD [6].

Cognitive impairment already defines the early stages of PD. In the Luxembourgish PD cohort, approximately 45% of newly diagnosed typical PD patients (disease duration ≤1 year) presented cognitive impairment (Montreal Cognitive Assessment (MoCA)<26). These findings are in line with previous observations of 24 to 54% of cognitive impairment in newly diagnosed PD [6–9]. These deficits may precede clinical PD diagnosis by up to 5 years [3]. Longitudinal studies comparing converters to non-converters describe a prevalence of 42% of cognitive impairment at baseline [7]. Knowledge on the nature of these prodromal cognitive changes is still limited, probably due to the novelty of the concept. Recent studies on cognitive deficits in prodromal PD described that global cognition and diverse cognitive sub-domains, mainly executive functions, less frequently visuospatial functions, memory and language, may be prodromal cognitive features of PD [8–11]. The available studies are very heterogeneous in their study designs (e.g., recruitment strategies), study populations (e.g., age, education), neuropsychological assessments and the tested cognitive domains, complicating the comparability of results [12–14]. Therefore, following previously published recommendations [5, 13], results on cognition in prodromal PD need validation 1) in a deep-phenotyped population, 2) combining predefined prodromal markers, 3) on normative-controlled cognitive data, 4) based on a broad variety of commonly used cognitive assessment tools to evaluate both global cognition and domain-specific cognition, and 5) with at least two tests per cognitive domain.

In the present cross-sectional, case-control study, we performed extensive cognitive testing in an at-risk group for developing PD, defined by probable RBD and hyposmia and compared them with an age- and sex-matched control group. Besides testing different cognitive functions, we investigated additional features such as non-motor (e.g., psychological factors and quality of life) and motor symptoms.

The main aim of this study was to describe non-motor symptoms in P-PD and to define its specific profile focusing on cognition. In the future, participants will be followed-up yearly to capture possible phenoconversion from P-PD to PD, allowing us to determine specific patterns supporting the definition of further possible prodromal markers. Early recognition of PD could not only allow better prognosis but also help the development of neuroprotective therapies.

METHODS

RESULTS

For Set 1, in total, 271 participants fulfilled the inclusion criteria, 76 participants with probable RBD and hyposmia and 195 control subjects without RBD and without hyposmia (Supplementary Figure 1A, B).

DISCUSSION

The aim of the present study was to investigate non-motor symptoms focusing on the cognitive profile in a prodromal PD (P-PD) cohort with self-assessments and extensive cognitive testing. We compared presence and level of non-motor symptoms, focusing on cognition, between P-PD and age- and sex-matched control subjects. The present study demonstrates that cognitive performance was impaired in the at-risk group for developing PD compared to the control group. More precisely, participants with P-PD present significantly lower scores in global cognition, executive and visuo-constructive functions (in tasks with higher complexity) compared to the matched control group. In addition, we observed significantly more difficulties in motor and other non-motor symptoms of experiences of daily living, as well as significantly higher scores for depression and apathy and significantly lower scores for quality of life in the P-PD group.

The observation of global cognitive and executive deficits are consistent with the conclusion of recently published studies stating that these cognitive impairments may be prodromal features of PD [8–10, 30]. With the screening tool for global cognition (MoCA) employed here, we observed that 40% of the at-risk group presented cognitive impairment, in contrast to only 15% in the matched control group. These results are consistent with findings of 42% with MCI and global cognitive deficit at baseline in a longitudinal study comparing converters to non-converters [7] and close to the prevalence of 45% of MCI in newly diagnosed PD patients in our PD cohort [15]. A longitudinal study on RBD P-PD participants found that global cognitive deficits appeared approximately 5 years before phenoconversion to PD compared to age- and sex-matched control subjects [3].

We found tendencies for impaired executive functions in P-PD across all assessments previously defined to evaluate these functions. After correction for multiple testing, significant differences remained for one sub-domain of executive functions: mental flexibility, as measured by the Trail-Making-Test (TMT). Therefore, we carefully interpret that, out of a range of neuropsychological assessments of executive functioning, the TMT might be the most sensitive for detecting executive changes in P-PD. Our findings of significantly impaired mental flexibility and a trend towards impairment in other sub-domains of executive functions are in line with observations in longitudinal and cross-sectional studies in prodromal PD cohorts [8, 31]. Furthermore, they match with the cognitive profile of an executive deficit in newly diagnosed PD patients [32] and its association to the frontal lobe and modulation by dopaminergic input [33]. Our observations of early pre-diagnostic impairment of executive functions lend support to the “Dual Syndrome Hypothesis” [34], describing the possibility of two sub-types of cognitive impairment in PD; the “frontal-striatal subtype”, defined by predominant executive deficits related to increased dopaminergic loss starting early in the disease progression; and the “posterior and temporal subtype” with predominant visuospatial, memory and language deficits, related to increased cholinergic loss [34]. In the present study, we did not find significant differences in processing speed, language, learning and memory. Only a few studies tested learning and memory [10–13, 30]. Memory impairments have been observed in patients who converted to PD within 2 years but not in the earlier prodromal stages [35]. Based on the results in Set 2, by applying the CUPRO evaluation system [22], we confirmed that the significant difficulties observed in the Cube Copying Task (initial scoring on 1 point [24]) are due to visuo-constructive deficits and not to a deficit of retrograde procedural memory. To our knowledge, the current study is the first to systematically evaluate retrograde procedural memory in P-PD. Given that, in our previous work on retrograde procedural memory in already diagnosed PD, we did not see any significant correlation between this memory concept and disease duration [22], we assumed that retrograde procedural memory might be already impaired in the prodromal stages of PD.

The combination of the absence of memory and language impairment, the visuo-constructive impairment only in the more complex assessments and the previously discussed point of a more “frontal-striatal subtype” suggest that the sample may still be in the early stage of P-PD. Previous findings demonstrated that motor variables have been found to be highly predictive of the phenoconversion to parkinsonism [36]. The fact that we did not see any significant differences for the measured motor assessments (UPDRS part III) and that the UPDRS score is estimated to become only abnormal at 4.5 years before diagnosis [37] are further arguments highlighting the possibility that the cohort is in the early stage of P-PD. This might be explained by our wide study design defining the prodromal cohort based on a population-wide participant recruitment in which we invited the entire Luxembourgish population between 55 and 75 years to participate in an online survey about their sleep quality and possible sleeping difficulties. One additional fundamental strength of the current study is the thorough recruitment steps and deep phenotyping of the participants, involving a complex study design, including self-reported, web-based questionnaires, telephone interviews, face-to-face assessments, and longitudinal follow-up assessments. Moreover, by combining two validated prodromal markers, RBD and hyposmia, we work on a population that is at high risk to develop PD. Furthermore, as recommended [12], we assured that the groups were well described and matched for possible confounding factors such as age and sex. Domain-specific cognitive deficits were investigated each through several assessments, allowing us to cross-validate our results. While global cognition and executive functions have been frequently evaluated, learning, memory, visuo-spatial cognition, and language abilities are less frequently assessed [12, 13]. Although we administered an extensive range of neuropsychological assessments, we acknowledge that no cognitive assessment evaluates purely one cognitive function and impairments in one domain may be reflected in impaired performances on tests assessing other domains. Lastly, we cannot fully exclude the possibility of cognition in P-PD being affected by sleep problems and depressive mood. Sleep abnormalities and mood disorders such as depression are validated signs for P-PD [5, 6]. We repeated our regressions by additionally controlling for apathy and depression and the adjustment for apathy and depression does not change our conclusions on the effects of the disease status on the outcomes (significant vs. insignificant). Given that the study participants are characterized with sleep abnormalities and knowing that sleep quality plays a crucial role in the well-functioning of cognition, cognitive performance may be affected by these confounders [38].

Our study has the limitation that it focuses on an at-risk cohort based on probable RBD (pRBD) and not on a polysomnographically proven idiopathic RBD (iRBD). According to the MDS criteria for P-PD, iRBD based on polysomnography has a positive likelihood ratio of 130 compared to only 2.8 for the questionnaire-based pRBD [6]. Therefore, to follow the gold standard for RBD diagnosis and to enrich the prodromal cohort, participants with pRBD are currently undergoing video-polysomnography to confirm the diagnosis of RBD. Furthermore, given that our P-PD cohort is defined by pRBD and hyposmia, we need to highlight that our observations focus mainly on one specific subtype of P-PD, as we do not control for all potential prodromal markers and that it cannot be generalized on all the P-PD subtypes. Especially because iRBD in PD has been associated with higher burden of non-motor symptoms, such as impaired cognitive functions [36, 39]. In order to address the heterogeneity in P-PD, we are currently working on the investigation of a population based on additional prodromal signs, e.g.: by combining alternative prodromal signs, such as constipation and genetic predispositions [40]. Exploring different markers may yield valuable insights, particularly if they are associated with distinct cognitive patterns and varying degrees of severity [13]. Another limitation lies in the fact that not all participants with RBD might develop PD, as RBD is also a risk factor for other synucleinopathies, such as dementia with Lewy bodies or multiple system atrophy [41]. The understanding of the heterogeneity in P-PD is essential to understanding the diversity of clinical PD and the mechanisms behind this variability.

The trends described in the present study highlight the importance of investigating cognitive performances and other non-motor symptoms in populations at risk of developing Parkinson’s disease. However, as these findings are based on the cross-sectional analyses it needs validation on longitudinal observations. Therefore, we aim to confirm the reported findings through longitudinal follow-up, currently foreseen. Furthermore, for future projects, it would be interesting to also include subjective cognitive decline in P-PD, as little knowledge on prevalence and progression of subjective cognitive decline exists in P-PD [13], and to compare different risk factor profiles involved in P-PD.

In conclusion, our findings confirm that global cognitive, executive, and visuo-constructive deficits are more prevalent in individuals at risk for PD based on probable RBD and hyposmia. In addition, people with P-PD had significantly more self-reported motor and other non-motor symptoms, such as depression and apathy, and a lower quality of life. The validation of these results, on normative-controlled, extensive cognitive and clinical data in a deep-phenotyped population is essential, as knowledge on the nature of these cognitive changes is still limited due to the novelty of the concept of cognitive deficits in P-PD [14]. Combining non-motor prodromal signs, including global cognition, executive and visuo-constructive functions, depression, apathy, and quality of life may improve the description of the P-PD phenotype and allow a clearer identification of the at-risk population for PD. Based on our findings and if replicated in other samples, we suggest considering the addition of executive and visuo-constructive deficits as a non-motor sign in P-PD. A clear definition of the P-PD phenotype will have an important impact when disease-modifying treatments will become available [42].