Five new things

Purpose of review: While the distinctive motor symptoms of Parkinson disease (PD) have been described for centuries, cognitive impairment has only recently been recognized as a central feature. Studies have yielded clues to the etiology and natural history of cognitive impairment in PD, but much remains unclear and effective therapies are needed. Recent findings: Longitudinal cohort studies demonstrate that almost all patients with PDwill develop dementia if they live long enough. New CSF biomarker and genetic studies suggest that it may soon be possible to forecast and track the progression of dementia in PD. Sleep and sleep disturbance appear to be intrinsically linkedwith PD, although the implications for individual outcomes and opportunities for intervention are unclear. Multidisciplinary treatment approaches incorporating cognitive training may help to improve outcomes. Summary: We review several recent advances in understanding the pathophysiology, genetics, and management of cognitive impairment in PD. Neurol Clin Pract 2016;6:452–458 C ognitive impairment is a disabling comorbidity for many patients with Parkinson disease (PD) and represents a major challenge for physicians, caregivers, and the health care system. Prevalence and natural history of PD dementia: Near-universal prevalence and progression Clinical features of cognitive impairment in PD involve a wide range of cognitive domains, including executive function, visuospatial reasoning, memory, and language function, and can include additional features including visual hallucinations, paranoia, and fluctuations in attention. PD is often marked primarily by visuospatial and executive deficits, in contrast to Alzheimer disease (AD), where memory impairment predominates. Cognitive impairment in PD encompasses a spectrum of severity from relatively mild symptoms to end-stage Department of Neurology (AAD, BR), Washington University School of Medicine, St. Louis, MO; and School of Public Health (BR), University of the Witwatersrand, Johannesburg, South Africa. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. Correspondence to: racetteb@neuro.wustl. edu 452 © 2016 American Academy of Neurology a 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. dementia. Despite the controversy surrounding the nomenclature and clinical significance of the term mild cognitive impairment (MCI), careful characterization of early symptoms is needed for both research and clinical purposes, and formal criteria for diagnosis of MCI in PD have been established. Overall prevalence of PD-associated dementia (PDD) is approximately 25%–30% of total PD cases, and increases dramatically with advancing age. While some patients with PD survive a decade or more before developing dementia, others experience cognitive impairment shortly after, or concurrent with the onset of motor symptoms, leading to the arbitrary distinction of patients who develop dementia within 1 year of parkinsonism as having dementia with Lewy bodies (DLB). The Sydney Multicenter Study, the longest PD cohort study to date, found that 83% of patients who survived 20 years developed dementia. This and other studies, including a large retrospective study of Medicare beneficiaries, demonstrate that patients with PD are almost universally at risk of dementia if they survive long enough. Studies are mixed when assessing the individual contributions of age, age at onset of PD, and disease duration to the risk of dementia. These mixed findings make it difficult to draw conclusions regarding the importance of factors other than the chronic accumulation of PD pathology on the development of dementia. A recent study followed 141 patients with PD with normal cognition at baseline over a period of 2–6 years, finding that nearly half of participants developed cognitive impairment within 5 years, and that 100% of individuals who developed MCI progressed to dementia within 5 years. Consistent with other recent studies, predictors of progression from normal cognition to cognitive impairment included male sex, higher Unified Parkinson’s Disease Rating Scale motor score, and lower (poorer) baseline cognitive scores. Although comparisons of rate of cognitive decline across diseases are challenging, we note for reference that in cognitively normal patients with CSF biomarker evidence of preclinical AD, the 5-year progression rate to Clinical Dementia Rating 0.5 (very mild dementia) was between 11% and 26%. Further work is needed to address the relative relationships of PD-specific pathology vs other age-related neuropathology on the development of dementia in patients with PD. For example, nearly 60% of patients with PD with dementia have concurrent cortical Ab pathology. Nevertheless, these data emphasize that patients with PD progress quickly from normal cognition through stages of cognitive impairment, including dementia, and that dementia in PD contributes to greater public health burden than previously recognized. Biomarkers: An ongoing quest for molecular fingerprints PD remains a clinical diagnosis, with only one commercially available biomarker ([I]-ioflupane, a dopamine transporter radioligand) approved to distinguish PD from essential tremor, although the value of this biomarker compared to longitudinal follow-up with a movement disorders specialist is unclear. Neurologists, even experienced movement disorders specialists, are frequently inaccurate in distinguishing idiopathic PD from other parkinsonian syndromes, especially early in the disease course. Predicting the risk and timing of dementia in patients with PD is equally challenging and is complicated by the heterogeneity of molecular neuropathology observed in PDD cases when autopsy examination is used as a gold standard. While multiple studies support a direct relationship between the presence of cortical Lewy pathology and cognitive impairment, some patients with PDD have very few cortical Lewy bodies. Conversely, extensive cortical Lewy pathology is occasionally seen in cognitively normal patients with PD and even individuals without PD. These observations suggest that a-synuclein (aSyn) is not solely responsible for cognitive impairment in PD. Multiple studies have documented the presence of concomitant b-amyloid (Ab) in approximately 60% of patients with PD with dementia, as well as tau pathology in a smaller subset, underscoring the need for accurate biomarkers to define molecular disease signatures prior to autopsy, ideally in presymptomatic or early symptomatic phases. Neurology: Clinical Practice ||| October 2016 Neurology.org/cp 453 Parkinson disease and cognitive impairment a 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Several recent studies report associations between CSF biomarkers and risk of cognitive decline in PD. In approximately 300 participants from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, investigators found that higher CSF aSyn levels predicted worse cognitive performance at follow-up, despite average length to follow-up of only 1.8 years. Another DATATOP study found that CSF levels of phospho-tau and phospho-tau/Ab42 ratio predicted decline in cognitive tasks over approximately 4 years. Notably, this was the first study to show an association with CSF tau and progression of cognitive impairment in PD, building on previous reports documenting higher CSF tau levels in patients with PDD than in patients with PD without dementia and controls. Another smaller prospective study found that lower CSF Ab 1–42 (Ab42) and higher aSyn levels at baseline predicted cognitive decline over 2 years. In this study, higher baseline levels of CSF phospho-tau were associated with worsening of motor but not cognitive symptoms. Although these findings demonstrate the potential value of CSF biomarkers for cognitive impairment in PD, there are several caveats. First, the duration of follow-up was relatively short, compared to the timeframe over which many patients with PD develop dementia, so the generalizability to the full spectrum of cognitive decline in PD is unclear. As such, these biomarkers may better reflect accelerated cognitive decline and could potentially be useful for prognostication in cases of rapid cognitive decline. Most studies have been based on clinical diagnoses and not neuropathologic criteria, which has been shown repeatedly to be the gold standard for diagnosis of neurodegenerative disease. While CSF data have the advantage of an objective molecular marker, future studies will hopefully be combined with pathology, and especially pathologic burden, to further increase our understanding of the molecular signatures of PD and PDD. Genetics: Renewed importance of APOE; GBA variants and potential role of lysosomal dysfunction Given the overlap in clinical symptoms and neuropathologic features among PDD, AD, and DLB, genetic association studies represent a powerful tool to identify areas of potential divergence in molecular mechanism and to highlight shared genetic risk factors that may represent common neurodegenerative pathways. A recent multicenter study of neuropathologically confirmed DLB cases reported 3 genetic loci with significant associations with the DLB phenotype, corresponding to the genes for APOE (odds ratio [OR] 2.786, 95% confidence interval [CI] 2.397–3.239), aSyn (SNCA; OR 0.754, 95% CI 0.6725–0.8468), and SCARB2 (OR 0.749, 95% CI 0.658–0.854), a lysosomal protein previously linked to PD. Another study found that the APOE e4 allele associated with DLB regardless of the presence of Ab pathology, suggesting that APOE may have an Ab-independent effect on DLB and PDD pathogenesis. The importance of APOE was further underscored by the finding that the APOE e4