Although a detailed discussion of neuroimaging and neurophysiological markers is beyond the scope of this chapter, we want to point out that increasing evidence supports the potential usefulness of structural MRI , SPECT , PET , or quantitative EEG  in predicting cognitive decline and dementia in PD (see Chapter 10). These techniques are considered attractive because they are not very invasive and can be combined with neuropsychological measures or wet biomarkers in order to optimize prognostic accuracy. Indeed, one recent longitudinal study demonstrated that baseline abnormalities in three different modalities (CSF A^42, volumetric MRI, neuropsychological impairment) combined separated perfectly PD patients who did or did not develop PD-D during 18 months of follow-up . Despite the small cohort and short follow-up, these findings are encouraging for future research and support the notion that combining biomarkers from different modalities is superior to single measures in predicting PD-D.
This review shows that considerable efforts have been made to identify cognitive biomarkers in PD. A range of biochemical markers are now available that are thought to reflect key mechanisms in the pathogenesis of PD-D. However, although several promising markers have been identified, findings have not been replicated or are inconsistent for the vast majority of candidates. This lack of consistency may be due to a number of reasons from bench to bedside, including variability in pre-analytical or analytical procedures, patient characteristics, range and choice of cognitive tests, and definitions of PD-MCI and PD-D. This hampers the comparability of studies, and also the possibility for collaboration between different study sites. The harmonization of laboratory and clinical procedures will be important for the translation from biomarker discovery to validation and eventually use in clinical routine.
In addition to variability in pre-clinical and clinical procedures, the scarcity of prospective longitudinal studies for the majority of explored markers represents another major limitation in the search for clinically useful cognitive biomarkers in PD. Indeed, because current evidence on cognitive biomarkers is dominated by cross-sectional studies, the predictive value of most markers is unknown.
The slowly progressive nature of the disease and the substantial biological and clinical heterogeneity per se make the search for biomarkers in PD challenging. For example, some patients develop dementia within a couple of years of diagnosis whereas others remain cognitively normal for more than two decades. For these reasons, large-scale studies that follow patients over a long period of time, ideally from diagnosis to death, are needed. In such studies, repeated assessment of biomarkers is desirable, not only in the search for markers that may help to track cognitive decline but also because changes in biomarkers over time might be a more powerful predictor of subsequent progression to dementia. However, such studies are difficult to perform at single centres and demand collaboration between multiple study sites and possibly countries. One important example of such a multicentre international cooperation is the Parkinson’s Progression Markers Initiative .
Finally, the genetics, neuropathology, and biochemistry underlying cognitive changes in PD are complex and therefore best covered by combined assessments of multiple biomarkers from different modalities. These could be further combined with genetic, demographic, and clinical risk factors in order to identify those patients at highest risk for PD-D as early as possible during the course of their disease (Fig. 11.1). This would not only be important for patient management and efficient recruitment to clinical trials testing therapies to prevent PD-D, but also for timely initiation of such treatments once they become available in the future.
Fig. 11.1 Cognition markers.