Sleep disturbances, cognitive decline, and AD biomarkers alterations in early Parkinson's disease

Abstract Objective We aimed to investigate whether each type of sleep disturbances (i.e., pRBD, EDS, and insomnia) is specifically associated with faster decline in global cognition and different cognitive domains among de novo PD patients. We also assessed the influence of sleep disturbances on core AD CSF biomarkers alterations and conversion to dementia. Methods Prospectively longitudinal data were obtained from the PPMI cohort. Sleep disturbances and cognition ability were assessed by questionnaires at baseline and follow‐up visits. Generalized linear mixed models were utilized to assess the effect of sleep disturbances on cognitive decline and core AD CSF biomarkers change. The associations between sleep disturbances and conversion to dementia were analyzed using Cox regression analysis. Results Baseline pRBD was associated with faster decline in global cognition and all cognitive domains, including verbal episodic memory, visuospatial ability, executive function, language, and processing speed. EDS was associated with faster decline in three cognitive domains, including verbal episodic memory, executive function/working memory, and processing speed. Insomnia was associated with faster decline in global cognition and verbal episodic memory. Meanwhile, pRBD and EDS were associated with longitudinal decrease of CSF Aβ42. Baseline pRBD increased the risk of conversion to dementia. The risk of dementia in PD patients with multiple sleep disturbances also increased compared with those without sleep disturbance. Interpretation Sleep disturbances (i.e., pRBD, EDS, and insomnia) were associated with cognitive decline in early PD. EDS and pRBD were associated with decrease of CSF Aβ42. Moreover, pRBD was associated with conversion to dementia.


Introduction
Although Parkinson's disease (PD) is defined by its motor manifestation, nonmotor symptoms are common and have a profound effect on patient experience and quality of life. 1 Sleep disturbances and cognitive impairments are among the most common of these symptoms, with major consequences for patients as well as relatives and caregivers. 2,3Sleep disturbances affect up to 98% of PD patients. 4The sleep disturbances affected in PD include both nocturnal manifestations, such as insomnia, REM Sleep Behavior Disorder (RBD), Obstructive Sleep Apnea (OSA) and Restless Legs Syndrome (RLS), and diurnal symptoms, such as Excessive Daytime Sleepiness (EDS). 50][11] Previous cross-sectional study revealed the relationship between RBD and poor performance in several cognitive domains, particularly in attention and memory in PD patients. 12BD in PD may be an important risk factor for mild cognitive impairment (MCI). 7Naismith et al. have noted that EDS is a significant predictor of slowed processing speed in PD patients. 13Thus, the type and extent of cognitive deficits seem to vary widely among different types of sleep disturbance in PD.Specific sleep disturbance may have differing effects on different cognitive domains.Most previous studies that investigated the association between sleep disturbances and cognitive abilities were cross-sectional studies that only included patients in the moderate to severe stages of disease. 12,14High-quality longitudinal cohort studies and evidence from the early stages of PD are relative limited. 14Chahine and his colleague reported that p-RBD could predict greater annual rate of decline in MoCA score during 3-year follow-up. 15owever, data from the same cohort showed that EDS was not longitudinally associated with cognitive dysfunction in early PD. 16esides the PD-defining synuclein pathology, other age-related neurodegenerative pathologies can coexist in PD brains including amyloid beta (Ab) and tau pathology that are classical features of AD. 17 Increasing evidence showed the diagnostic usefulness of CSF biomarkers in AD, which provides a great impetus to implement CSF biomarkers in other neurodegenerative disorders such as PD. 18,19The cerebrospinal fluid (CSF) Ab 1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau) have been reported to be associated with cognitive impairment in PD. 20 Low levels of CSF Ab42 of nondemented PD patients predict development of cognitive impairment over time. 21CSF AD biomarkers may play a role in the relationship between sleep disturbances and cognitive decline in PD.
On the basis of these considerations, in this study, we aimed to undertake longitudinal assessments in a cohort of de novo PD patients, with a follow-up period of 5 years.We aimed to investigate whether each type of sleep disturbances (i.e., pRBD, EDS, and insomnia) is specifically associated with faster decline in global cognition and different cognitive domains.We also determined the specific relationship between different sleep disturbances and core AD CSF biomarkers alterations.The influence of sleep disturbances on conversion to dementia over time was also evaluated.

Methods
Study participants and study design either an asymmetric resting tremor or asymmetric bradykinesia, (4) have dopamine transporter deficit on dopamine transporter imaging, and (5) have Montreal Cognitive Assessment (MoCA) >26 at baseline.PPMI inclusion criteria for healthy adults also require MoCA >26 at baseline. 22In addition, all PD patients were followed up for 5 years.The PPMI study and protocols were approved by the local ethics committees, and written informed consent was provided from each participant before being included in the study.All methods in this study were carried out in accordance with relevant guidelines and regulations.

Clinical and neuropsychological assessment measures
The sleep disturbances assessed include EDS, insomnia, and pRBD.EDS was assessed using the Epworth Sleepiness Scale (ESS), a validated measure of EDS in which participants rate their likelihood of falling asleep in eight situations. 24Participants were categorized as having EDS if ESS was ≥10. 25 Insomnia complaints were evaluated using subitem 1.7 of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 26 .Participants were asked: "Over the past week, have you had trouble going to sleep at night or staying asleep throughout the night?Consider how rested you felt after waking up in the morning."Clinically relevant insomnia was defined as a MDS-UPDRS subitem 1.7 score ≥2, which was previously used 27 and shown to have good correlation with other insomnia rating scales. 28The presence of pRBD was assessed using the RBD Screening Questionnaire (RBDSQ), 29 a widely used tool to assess RBD symptoms and has been validated in several populations, demonstrating both high sensitivity and specificity. 30,31We defined pRBD as RBDSQ scores >5. 30europsychological tests were performed to assess global and domain-specific cognitive status, including: the MoCA for global cognition; the Hopkins Verbal Learning Test (HVLT) Total Recall, HVLT Delayed Recall, and HVLT Recognition for verbal episodic memory; the Judgment of Line Orientation (JoLO) for visuospatial ability; the letter-number sequencing (LNS) for executive function/working memory; the semantic fluency test for language; and the symbol digit modalities test (SDMT) for processing speed/attention.For all these tests, a higher score implied a better cognitive performance.All these cognitive tests were assessed at baseline and follow-up visits.Cognitive status of participants was classified based on the criteria used in previous literature [32][33][34]

Statistical analysis
For the demographic and clinical characteristics at baseline, descriptive statistics were expressed as mean AE standard deviation (SD) for continuous variables and as percentage frequency for categorical variables.For between-group comparisons of demographic and clinical variables, Mann-Whitney U tests and chi-square tests were used.Generalized linear mixed models (GLMM) were utilized to assess the effect of baseline sleep disturbances on cognitive performance decline and core AD CSF biomarkers change over time.These models interpreted the correlations between repeated measures and variables over time.The predictive power of sleep disturbances on cognitive decline and core AD biomarkers change was analyzed via interactions with visit time, thus revealing the influence of sleep disorders on cognitive score and core AD biomarkers changes over time.The associations between type or number of sleep disturbances and conversion to dementia during follow-up were analyzed using Cox regression analysis.The cumulative incidence of dementia among various groups during follow-up was compared using Kaplan-Meier survival curves.Bonferroni correction was applied for those multiple comparisons between groups.All GLMM and Cox regression analysis were subject to adjustments for confounding variables, including age, gender, education, age of onset, and APOE ɛ4 carrier status.All data were analyzed via SPSS 26.0, and the statistical significance threshold was set at p < 0.05.

Results
A total of 413 patients with de novo PD and 196 healthy adults were recruited at baseline, and 383, 366, 354, 333, and 305 PD patients were followed up at 1, 2, 3, 4, and 5 years, respectively.The baseline demographic and clinical characteristics of the study cohort were described in Table 1.The average age of patient with de novo PD was 61.53 AE 9.68 years, with a male proportion of 65.1%.Patients with de novo PD had a lower score of MoCA (p < 0.001), HVLT Total Recall (p < 0.001), HVLT delayed recall (p < 0.001), HVLT recognition (p < 0.001), and SDMT (p < 0.001) than healthy adults.There were significant differences between these two groups in the levels of CSF T-tau (p = 0.001), P-tau (p = 0.029), and Ab42 (p < 0.001).Additionally, significantly more PD patients reported pRBD compared with healthy adults (p < 0.001).
Insomnia was associated with cognitive decline during follow-up.The MOCA score in PD patients with insomnia decreased by 0.453 points per annum when compared with those without insomnia (b = 0.453, p < 0.001) (Table 2).With regard to specific cognitive tests, patients with insomnia experienced greater declines in HVLT delayed recall and HVLT recognition.There is no significant difference in the MoCA score change between PD patients with and without EDS.With regard to specific cognitive tests, patients with EDS experienced significantly greater declines in LNS and SDMT.Additionally, baseline EDS predicted the longitudinal decrease of CSF Ab42.Baseline pRBD was also associated with cognitive decline over time.Patients with pRBD experienced a reduction in MOCA score of 0.758 points per annum when compared to those without pRBD (b = 0.758, p < 0.001).With regard to specific cognitive tests, patients with pRBD experienced significantly greater declines in HVLT total recall, HVLT delayed recall, HVLT recognition, JoLO, LNS, semantic fluency test, and SDMT.Baseline pRBD also predicted the longitudinal decrease of CSF Ab42.
To determine the potential of sleep disturbances to serve as predictors of conversion to dementia in de novo PD patients, Cox regression analysis was performed.The crude Cox model showed that there is significant difference in the hazard of conversion to dementia between PD patients with and without pRBD (HR 1.327, 95% CI 1.13-3.346,p = 0.016) (Table 3).However, no significant predictive effect of insomnia and EDS on the risk of dementia was found.Similar findings were demonstrated by the adjusted Cox models.Patients with pRBD at baseline had a greater risk of dementia compared with those with no pRBD (HR 1.785, 95% CI 1.032-3.087,p = 0.038), while adjusting for age, gender, education, age of onset, and APOE ɛ4 carriers.The hazard for dementia in patients with insomnia tended to higher than those without insomnia, but the difference did not reach statistical significance (HR 1.661, 95% CI 0.923 to 2.987, p = 0.091).
To determine the association between number of sleep disturbances and risk of conversion to dementia in PD patients, we performed Kaplan-Meier survival curves and Cox regression analysis.PD patients were grouped into whether they reported none, one, and multiple (two or three types) sleep disturbances at baseline.Table 4 shows the incidence of dementia and the HR for conversion to

Discussion
In the present study, we assessed the longitudinal associations of sleep disturbances with cognitive decline, core AD CSF biomarker alterations, and conversion to dementia among de novo Parkinson's disease patients over time.
We found that pRBD in PD was related to faster decline in global cognition and all cognitive domains, including verbal episodic memory, visuospatial ability, executive function/working memory, language, and processing speed/attention.EDS was associated with faster decline in three major cognitive domains, including verbal episodic memory, executive function/working memory, and processing speed/attention.Insomnia was associated with faster decline in global cognition and verbal episodic memory.Meanwhile, pRBD and EDS were observed to be associated with longitudinal decrease of CSF Ab42.Baseline pRBD increased the risk of conversion to dementia.The risk of dementia in PD patients with multiple sleep disturbances also increased over time compared with those without sleep disturbance.RBD is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. 36The prevalence of RBD ranges from 33% to 46% in PD patients when diagnosed with polysomnography (PSG). 37Xu et al. reported a progressive increase in the frequency of RBD in de novo PD patients over time. 38Despite growing evidence revealing a cross-sectional relationship between RBD and cognitive impairment in PD patients, little is known of the specific aspects of this longitudinal association.Folle et al. 39 reported that pRBD features are a clinical marker for faster cognitive decline in PD patients, but they did not investigated the influence of RBD on specific cognitive domains over time.In this study, we found that RBD was associated with faster decline in global cognitive functioning and all cognitive domains over time.These cognitive profile reflects the effect  of RBD on both frontostriatal and posterior cortical deficits.
A key question to consider is why patients with RBD are more likely to experience cognitive decline.The mechanisms underlying the association between cognitive decline and RBD in PD remain to be determined.Prior literature suggested that RBD and more severe memory deficits in PD may be epiphenomena of the degeneration of nondopaminergic systems and of altered temporal network. 40,41Executive deficits may be due to the abnormalities in subcortical and prefrontal structures in PD. 42 Relationship between abnormalities in subcortical structures (e.g., caudate nucleus, thalamus, and putamen) and the occurrence of RBD has been established. 43Faster decline in visuospatial ability tasks observed in PD patients with RBD could be the consequence of the posterior cortical damage. 41We found that pRBD was associated with an increased risk of conversion to dementia in de novo PD patients.Our findings are in line with other longitudinal studies suggesting that the presence of RBD in subjects with PD is an important clinical risk factor for the development of dementia. 44,45We also found that PD patients with multiple sleep disturbance had an increased risk of dementia compared with those without sleep disturbances.This finding suggests the multiple sleep disturbances have a cumulative effect on cognitive decline over time in de novo PD patients.Substantial data are available on the cross-sectional associations of EDS and insomnia with cognitive impairments in more advanced stages of PD. [46][47][48][49] Naismish et al. found that EDS was associated with worse performance on processing speed, 13 whereas another study reported that excessive daytime napping was related with worse executive control performance. 47A lack of consensus in the literature on these cross-sectional associations may be mainly due to methodological differences and limits between the studies.Our study represents the largest of prospective cohort study of de novo PD patients that investigated the influence of insomnia and EDS on global cognition and all cognitive domains over time.We found that EDS and insomnia give rise to faster decline in different cognitive domains.EDS was associated with faster decline in three major cognitive domains, including verbal episodic memory, executive function/working memory, and processing speed/attention.Insomnia was associated with faster decline in global cognition and verbal episodic memory.These results pointed to the fact that EDS is not simply a consequence of insomnia or a poor night's sleep, and the influence of EDS and insomnia on cognitive decline may be driven by a different mechanism.However, using data from PPMI cohort, Amara et al. reported that EDS was not associated with cognitive dysfunction longitudinally. 16This may be due to that they only assessed the global cognition with MoCA scores over the 3 years.
One novel aspect of this study is the inclusion of CSF biomarkers data.In the multivariate analysis, the only core AD biomarker that was associated with EDS and pRBD was longitudinal decrease of CSF Ab42.No association was found with T-tau and P-tau.The pathophysiology is multifactorial but aggregation of misfolded a-synuclein is considered to be a key underpinning mechanism in PD.AD pathology is also found in a considerable portion of patients with Parkinson's disease (PD), particularly those with cognitive impairments and early dementia (PDD). 20,50A convergence of evidence suggested that low CSF Ab42 is predictive of cognitive decline in nondemented PD patients. 21,51Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, are a useful predictive biomarker for cognitive decline. 21Thus, the longitudinal association between sleep disturbance and cognitive decline may be partly explained by the role of cerebral Ab deposition in PD.
Strengths of this study include the large sample size and comprehensive longitudinal clinical and biomarker assessments.There are, however, some limitations.While the MDS-UPDRS subitem 1.7 was previously used to screen clinically relevant insomnia 27 and shown to have good correlation with other insomnia rating scales, 28 EDS and RBD were not assessed using any objective measures.As this was a longitudinal cohort study that featured 5 years of follow-up, some questionnaire scales and biomarker measures were missing due to the long follow-up time.The inclusion criteria for healthy adults require MoCA >26 at baseline in PPMI cohort; thus, the comparison on cognition between PD patients and healthy adults may be not representative.

Conclusions
Sleep disturbances (i.e., pRBD, EDS, and insomnia) are associated with cognitive decline in de novo PD patients.EDS and pRBD were associated with longitudinal decrease of CSF Ab42.Moreover, pRBD was associated with an increased risk of conversion to dementia.

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2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Figure 1 .
Figure 1.Cumulative probability risk of conversion to dementia in the follow-up among PD participants.SD, sleep disturbances.

Table 1 .
Baseline demographic and clinical characteristics of PD patients and healthy adults.
Categorical variables are reported as numbers and percentages; continuous variables are reported as means AE standard deviations.p values were assessed by Mann-Whitney U tests and chi-square tests among the groups.The bold emphasis in the table means p < 0.05.APOE, apolipoprotein E; Ab42, amyloid-b42; CSF, cerebrospinal fluid; EDS, excessive daytime sleepiness; HVLT, Hopkins Verbal Learning Test; JoLO, Benton Judgment of Line Orientation; LNS, letter-number sequencing; MoCA, Montreal Cognitive Assessment; PD, Parkinson's disease; pRBD, probable REM sleep behavior disorder; P-tau, phosphorylated tau; SDMT, Symbol Digit Modality Test; T-tau, total tau.

Table 2 .
Longitudinal association of sleep disturbances with cognitive decline and core AD biomarkers alterations.
In these models, sleep disturbance is the independent variable, and the cognitive score and CSF biomarker is the dependent variable; age, gender, education, age of onset, and APOE ɛ4 carriers are covariates.The regression coefficients (b) and adjusted p values were assessed by generalized linear mixed models.The bold emphasis in the table means p < 0.05.Ab42, amyloid-b42; CI, confidence interval; CSF, cerebrospinal fluid; EDS, excessive daytime sleepiness; HVLT, Hopkins Verbal Learning Test; JoLO, Benton Judgment of Line Orientation; LNS, letter-number sequencing; MoCA, Montreal Cognitive Assessment; pRBD, probable REM sleep behavior disorder; P-tau, Phosphorylated tau; SDMT, Symbol Digit Modality Test; T-tau, total tau.

Table 3 .
Longitudinal association of type of sleep disturbance with conversion to dementia.
Adjusted models: age, gender, education, age of onset, and APOE ɛ4 carriers as covariates.The HR and adjusted p values were assessed by cox regression models.The bold emphasis in the table means p < 0.05.CI, confidence interval; EDS, excessive daytime sleepiness; HR, hazard ratio; pRBD, probable REM sleep behavior disorder; 1834 ª 2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Table 4 .
Longitudinal association of number of sleep disturbances with conversion to dementia.Adjusted models: age, gender, education, age of onset, and APOE ɛ4 carriers as covariates.The HR and adjusted p values were assessed by cox regression models.The bold emphasis in the table means p < 0.05.CI, confidence interval; HR, hazard ratio; SD, sleep disturbance.