Neuropsychological Characterization of Evolving Cognitive Decline in Idiopathic REM Sleep Behavior Disorder Is Important, But Not Easy

There is ample evidence of the RBD-neurodegenerative disease association, and RBD associated with the synucleinopathies is particularly strong.^1–4 Many patients with isolated RBD, often termed “idiopathic RBD” and abbreviated “iRBD”, subsequently develop cognitive impairment and/or parkinsonism, which is typically manifested as the syndromes of mild cognitive impairment (MCI), MCI with parkinsonism, dementia with Lewy bodies (DLB), Parkinson disease (PD), or PD with dementia.⁵ Investigators are increasingly attempting to identify the earliest features of an evolving neurodegenerative syndrome in those with iRBD, as such information permits better understanding of disease burden, progression, and prognostication.

Neuropsychological testing can be viewed as a biomarker, and impairment in one or more cognitive domains is a critical correlate for the identification of evolving MCI or dementia due to an underlying neurodegenerative disorder. Impairment can also precede overt neurobehavioral dysfunction, thus providing a means to identify those patients who will likely become symptomatic in the near future. The article authored by Fantini and colleagues⁶ in this issue of SLEEP provides important insights into the early and presumably clinically inapparent neurocognitive deficits in those with iRBD. These investigators compared neuropsychological test scores between a group of iRBD subjects (n = 24) to a group of normal control subjects (n = 12) at baseline, and at follow-up evaluation approximately two years later. The main findings revealed significantly worse performance in the iRBD group compared to normal controls at baseline and follow-up on tasks of visuoconstruction and verbal memory. On follow-up, the iRBD group also performed worse on a visuospatial supraspan attention task. The number of subjects with abnormal scores in these cognitive tasks using an Equivalent Score method was also greater in those with iRBD than in the normal control group. No data on the longitudinal course of specific subjects were provided.

Whether this group of patients with iRBD will develop other features consistent with an evolving neurodegenerative disorder remains to be seen. It may be anticipated that other features of Lewy body disease (LBD) will develop in many by virtue of the higher prevalence of LBD compared to other diseases associated with RBD.⁵ Cross-sectional analyses in iRBD subjects and in those with RBD associated with MCI or dementia have revealed a relatively consistent pattern of neuropsychological profiles. The dementia phenotype associated with RBD is usually DLB, in which impairment in attention/executive functioning and visuoconstructive/visuospatial functioning is typical.^7–9 These same domains tend to be affected in those patients with RBD who are also diagnosed with MCI,¹⁰ including those with MCI who subsequently develop the full DLB syndrome and ultimately have pathologic evidence of Lewy body disease.¹¹ Yet among those with RBD plus MCI, there is some degree of neuropsychological variability, with some presenting with only one domain affected, while others may have additional impairment in learning and memory.¹¹ As shown in the article by Fantini et al.,⁶ and as previously demonstrated,^12–14 the domains of learning and memory, attention/executive functioning, and visuoconstructive/visuospatial functioning can be affected in the asymptomatic/minimally symptomatic cognitive phase. Therefore, these data substantiate the utility of neuropsychological testing in identifying iRBD patients who likely have an underlying neurodegenerative disorder, which is probably underlying LBD, particularly when these cognitive domains are impaired.

These hypotheses have yet to be proven, and many questions remain. Among those with iRBD, when is impairment on neurocognitive performance first apparent? Which neurocognitive tests are optimal to use for early detection, and which are optimal to characterize decline over time? Importantly, the cross-sectional data suggest that there may be an evolution from asymptomatic/minimally symptomatic neuropsychological impairment, to MCI, and ultimately to dementia (as depicted in Figure 1). It is still uncertain, however, whether this progression actually occurs, and if so, whether it evolves in a predictable manner with a projected time course. This issue is crucial to the planning of future intervention studies. There is also a critical need to identify which affected neural networks underlie the neurocognitive deficits, and to determine the time course of changes in these pathological substrates relative to progression of neurocognitive impairments. These are some of many critical questions which will require comprehensive longitudinal studies in iRBD subjects—these questions could not be answered within the focused scope of the analysis by Fantini et al.⁶

Some of the observations in the data by Fantini et al. also underscore the challenges of longitudinal characterization, the spectrum of the underlying causes of iRBD and the variably associated neuropsychological deficits, and the variability of manifestations associated with neurodegenerative disorders themselves (such as LBD). The small sample size of the study also limits generalizability, and hence there remains a need for replication with further longitudinal clinical follow-up and neuropathologic examination. We commend Fantini and colleagues for assessing iRBD subjects in a standardized longitudinal manner, and urge increased identification of iRBD subjects and their participation in long-term comprehensive assessments involving neuropsychological testing and other potential biomarkers.