Differential effects of sex on longitudinal patterns of cognitive decline in Parkinson’s disease

Cognitive impairment is an often devastating and debilitating non-motor symptom of Parkinson’s disease (PD) [1, 2]. Upwards of 40% of people with Parkinson’s disease (PwP) develop some form of cognitive impairment, with a subset progressing from mild cognitive impairment (MCI) to a more severe Parkinson’s disease dementia (PDD) [1]. People often display executive dysfunction and attentional deficits in the early stages of the PD [3, 4] and progressively experience deficits in memory and visuospatial processing in the latter stages of the disease [3, 5]. However, cognitive deficits do not present in all PwP and can become apparent at any stage of the disease. Furthermore, the heterogeneity in both the presentation and rate of cognitive decline presents a challenge in the management and treatment of PD.

Studies examining demographic and clinical factors have identified increasing age, lower education levels, increasing disease duration, and motor symptom severity, among others, as contributing to susceptibility of cognitive impairment in PD [5]. Of these factors, patient sex not only influences disease risk [6, 7], but the presentation of several non-motor symptoms [8‐10]. Sex is known to be an important factor when considering cognition [11‐13], with sexual dimorphism observed across all ages in healthy populations [14‐16]. Although sex associations within PD are well reported, there is a lack of studies investigating sex-specific effects on individual cognitive domains, as well as longitudinal cognitive domain-specific decline in PD. Prior studies examining the effect of sex have been cross sectional in nature [5, 9, 10, 12, 17‐19], or have not considered the effect in various cognitive domains [20].

This study utilised a cohort of Australian PwP to assess the influence of sex on global and domain-specific cognitive performance. Further, a longitudinal subset of PwP was followed up to investigate the influence of sex on cognitive decline. It was thought that global and domain-specific sex differences in the architecture of cognitive ability and decline would be seen.

The occurrence of cognitive impairment is known to be an important determinant of morbidity and impaired quality of life in PwP, as well as having a major impact on caregiver burden. Furthermore, the heterogeneity of cognitive impairment risk and varied trajectory of cognitive decline with disease progression represents a difficult barrier in understanding and managing this facet of PD. Importantly, studies have noted sex as a risk variable in the onset of cognitive impairment, both in PD and in other populations. However, there have been few previous comprehensive investigations of sex-based differences in individual cognitive domains over time [31], as in the present study. Some prior studies have been purely cross sectional in nature [5, 9, 10, 12, 17‐19], while longitudinal studies have not examined the sex-specific differences in various cognitive domains [20], or have not focussed primarily on elucidating the impact of sex on cognition [32]. Here, our findings suggest that sex is a significant determinant of domain-specific cognitive performance, in agreement with prior literature. Furthermore, we show that sex is a significant predictor of cognitive decline over time, and of the likelihood of progressing to what may be considered a likely case of MCI. Interestingly, the proportion of females with cognitive scores that may potentially warrant a clinical diagnosis of MCI did not change longitudinally, highlighting the role of investigating cognition at the domain-specific level. Such sex-specific findings appear to explain some of the heterogeneity observed in the cognitive symptomatology of the disease, warranting further investigation into the underlying mechanisms of this sexual dimorphism.

Cross-sectional analysis in the present cohort revealed an association between sex and cognition, with males performing significantly worse than females in global cognition and in memory and fluency subdomains. Literature has reported sex differences in patterns of cognition in healthy young adults (ages 18–31) [15], as well as in adulthood and the ageing population [16]. In recent studies, young females were found to exhibit superior nonverbal reasoning skills and faster language decision-making than their male counterparts [14, 15], a finding that has also been reflected in older cohorts [16]. To explain these differences, neuroimaging studies have reported divergent patterns of brain connectivity, with males exhibiting a greater connectivity between the left superior parietal lobule (SPL) and posterior superior temporal gyrus (STG), whereas females had a greater connectivity between the left inferior frontal gyrus (IFG) and posterior STG [15, 33]. Furthermore, it was apparent that sex differences existed in inhibitory connections in these same regions. Apart from the SPL, such regions are typically associated with semantic fluency and language ability. The left posterior STG specifically contributes to the ability to produce sounds that form words (lexical phonology), as well as language comprehension and working memory [34, 35], and the functional connection between the IFG and posterior STG is involved in speech and language processing [36]. Whereas, the SPL is thought to be involved in spatial and visual perception [34]. These sex differences in structural and functional connectedness and networks may provide an explanation for the current findings of sex-specific changes in cognitive performance [13], whereby females had superior performance in fluency and memory. For instance, in the context of Parkinson’s disease, a number of the aforementioned structures have been implicated in patients with MCI and PDD [37, 38]. Notably, it has been reported that PwP who have MCI are more likely to have cortical thinning, particularly in the STG [39, 40]. Moreover, findings from the CamPaIGN study indicate that fluency tasks, which recruit structures of the temporal lobe, are associated with clinical presentation of cognitive impairment over time [5], results that are also reflected in the current cohort.

When examining cognition changes longitudinally in PwP, sex appeared to be a significant predictor of cognitive ability over time regardless of which domain was assessed. Overall, in global cognitive measures, males were noted to decline significantly more than females. Furthermore, it was observable that a higher proportion of males progressed to what could be considered as MCI, a clinically recognisable form of cognitive impairment. Such findings are reflective of current literature [9, 10, 17, 20]. Researchers have cited the neuroprotective effects of oestrogen as potentially playing a role in this effect [11, 13]. Not only have oestrogens been found to play a role in dopaminergic neurodegeneration in PD, but the hormone has been found to have favourable effects on neuroinflammation, oxidative stress and iron metabolism within the context of PD [41]. Furthermore, sex differences in microglial and astrocytic cells, such as their heightened sensitivity to inflammatory stimuli [42‐44] and their anatomical distribution [45, 46], have been postulated to mediate sex differences in cognition and memory [47, 48]. It is worthwhile considering that such results may be reflective of the superior baseline performance of females in cognitive measures than males or may be exacerbated by disease process, though prior research has found that sex-specific progression to cognitive impairment cannot be fully explained by this baseline performance, nor disease duration [31].

While previous studies have focussed on progression to a clinically diagnosable form of cognitive impairment, namely MCI or PDD, our findings point to noteworthy domain-specific effects of sex over time. Though males appeared to perform worse overall, what did vary between facets of cognition was which sex was protected, the directionality of cognitive ability, and the rate of decline. For instance, despite females exhibiting consistently superior overall cognitive performance at baseline, females had a greater decline in attention and orientation, memory, and visuospatial-perceptual ability over time, compared to males. Whereas, males had a greater decline in the language domain than females. These findings suggest that there is a differential sex-effect on domain-specific cognitive decline, but it remains to be determined what the implications of these differential patterns of decline are for progression to dementia. Though studying clinically distinguishable MCI and PDD is of importance, we see here that females do not progress to a state that may be indicative of MCI or PDD to the same extent as males; however, they do experience a greater decline in certain domains of their cognition than males. Such sex-specific effects on the architecture of cognitive decline may be of importance, and have not always been considered in the past. It is of particular interest because the decline seen in females here is in spite of their higher baseline scores and the putative neuroprotective effect of oestrogen. The role that this hormone plays in the sexual dimorphism reported in this study, predominantly in regard to the domain-specific rate and directionality of cognitive ability over time, remains elusive and represents an area which requires further investigation.

A number of limitations of the current study must be noted. First, at baseline, home-based PwP were recruited sequentially from three different movement disorder centres across Australia, which could have had the potential of introducing scoring variability. However, as the clinical assessments were performed by trained clinician-researchers this is unlikely to have had a significant impact on the data. Second, initial recruitment excluded individuals with more advanced PD and dementia, which is likely to have contributed to a lower mean age of symptom onset and higher cognitive scores at baseline, and the cohort is, therefore, not truly representative of a community-based sample. Further to this, follow-up recruitment were not able to include all baseline participants, in part this was due to the advanced nature of disease severity, which may introduce a degree of bias. In addition, the cohort was not recruited based upon sex, which has resulted in an uneven balance of male and female participants and may have altered findings. However, the proportion of males to females in the study is reflective of PD incidence in prior literature. In turn, despite being a contributor to cognitive functioning, education levels were not able to be obtained. Thus, were not included in statistical analyses. Finally, as the ACE-R includes a paucity of tests of executive function [27]. Therefore, the present findings should be confirmed using other more comprehensive cognitive testing protocols in larger longitudinal studies, while taking into consideration confounding variables that were not able to be included in this manuscript.

Here we report that sex is a significant determinant of cognitive decline in PD, both cross sectionally and in a repeated measures longitudinal study. Males were seen to perform significantly worse when considering disease course over time, and showed a greater likelihood than females of progressing to a probable case of MCI and PDD. However, it was apparent that in spite of maintaining a higher overall level of cognitive performance, females did experience a selective decline in certain cognitive domains with disease progression, highlighting the importance of examining for subclinical cognitive impairment. While the extent to which the differential effects of disease progression are responsible for the observed sex differences in cognition remains unclear, it is likely that PD-related cortical and subcortical pathology, coupled with age-related changes, may exacerbate sex differences in the severity and trajectory of cognitive decline. Overall, the results from this study support the consideration of sex in explaining some of the clinical heterogeneity observed in PD-related cognitive decline. Better understanding of the role of sex in the landscape of cognitive decline may help in stratifying different patterns of cognitive impairment and aid in the development of individualised treatment strategies for PwP.