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Biomarkers for cognitive impairment and dementia in Parkinson's disease

Guido Alves, Kenn Freddy Pedersen, and Jan Petter Larsen

Introduction

Cognitive impairment is one of the most frequent and disabling non-motor features in Parkinson’s disease (PD). Long-term observational studies indicate that up to 80% of PD patients develop dementia (PD-D) [1, 2]. PD-D evolves gradually, and many PD patients report mild cognitive impairment (PD-MCI) years before the onset of PD-D; this signals increased risk for progression to PD-D within 3-4 years, in both early [3] and advanced [4] disease stages.

While impaired episodic memory is the characteristic cognitive feature in patients with incipient Alzheimer’s disease (AD) [5], cognitive impairment in PD is more heterogeneous. Several large-scale studies in patients with newly diagnosed PD have revealed mild deficits in various cognitive domains, including attention and executive, memory, and visuospatial function, while language is less affected [6-8]. However, the profile of cognitive deficits in PD varies from patient to patient and may change over the course of the disease [9]. It has been proposed that cognitive deficits with a posterior-cortical basis rather than frontal-executive dysfunction predict subsequent development of dementia [10], yet this view is challenged by several longitudinal studies that also find executive and attentional deficits to herald an increased risk of PD-D [3, 11, 12].

Substantial inter-individual variability is also observed in the onset and progression of cognitive deficits, and the time from onset of motor symptoms to dementia varies considerably between individuals. Longitudinal studies indicate that about 20% of patients with PD develop dementia within 5 years of diagnosis [10], whereas another 20% are still without dementia after 20 years [1].

Biological heterogeneity

The clinical heterogeneity in PD probably reflects variability in the underlying neuropathological and biochemical changes. While loss of dopaminergic neurons in substantia nigra and aggregation of a-synuclein (aSyn) with the formation of Lewy bodies are the pathological hallmarks of PD, the disease is now recognized as a widespread, multisystem brain disorder that may cause multiple transmitter deficits from its very earliest stages. In addition, vascular lesions and AD- type changes, such as amyloid-beta (A^) and tau pathologies, are found post mortem in a number of patients with PD-D [13]. These pathologies have been proposed to influence the spread of aSyn and the rate of cognitive decline in PD [13]. The large inter-individual variability in risk and time to PD-D may further be explained by individual differences in the capacity of the brain to tolerate (‘cognitive reserve’) [14] or counteract these pathologies, for example through activation of the innate immune system or degradation of pathological protein aggregates [15]. Finally, clinical, biochemical and neuropathological heterogeneity in PD may be genetically determined, and several genetic polymorphisms that modify the risk of PD-D have been proposed.

 
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