Cognitive decline in Parkinson disease

Abstract

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition — or even reversal to normal cognition — is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment.

The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.


Parkinson disease (PD) is one of the most common age-related brain disorders. PD is defined primarily as a movement disorder, with the typical symptoms being resting tremor, rigidity, bradykinesia and postural instability, and is pathologically characterized by degeneration of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (misfolded α-synuclein) in the surviving neurons. In addition to the defining dopamine-related motor symptoms, however, PD is increasingly recognized as a heterogeneous multisystem disorder involving other neurotransmitter systems, such as the serotonergic, noradrenergic and cholinergic circuits. Thus, a wide variety of nonmotor symptoms (NMS) linked with these neurotransmitters are commonly observed in patients with PD. In light of this variability, subtyping of PD has been proposed, including a system based on time of onset and ongoing rate of cognitive decline1.

Cognitive decline is among the most common and important NMS, and in this article we review the current status of knowledge regarding cognitive impairment in PD. Robust evidence indicates that in comparison with age-matched groups without PD, people with PD exhibit more rapid decline in a number of cognitive domains — in particular, executive, attentional and visuospatial domains, but also memory. The full spectrum of cognitive abilities can be observed in PD, from normal cognition, through early mild subjective and objective decline (mild cognitive impairment (MCI)), to mild, moderate and even severe PD dementia (PDD). Studies from the 1990s onwards convincingly demonstrated a much higher cumulative risk of dementia in people with PD than in the general population, and systematic reviews showed that the point prevalence of dementia was 25–30%. Several long-term longitudinal studies have indicated that the majority of patients with PD will develop dementia if they survive for more than 10 years after diagnosis. On the basis of numerous, varied studies, we now know that dementia in PD has important adverse implications for functioning, quality of life, caregiver burden, and health-related costs2.

The timing, profile and rate of cognitive decline vary widely among individuals with PD, so identifying and predicting future cognitive decline in this population is crucial for researchers and clinicians alike. Identification of clinical and biological markers that can predict which patients are at increased risk of early and rapid cognitive decline is important for communicating the prognosis and managing patients clinically and, thus, is a focus of this article. Established demographic and clinical risk factors include increasing age and more severe parkinsonism, in particular, non-tremor features2. Here, we focus on cognitive and biomarker features as potential predictors of cognitive decline in PD.

Cognitive syndromes in PD

Subjective cognitive decline

In recent years, interest has focused on subjective cognitive decline (SCD), in which cognitive impairments are noted by the patient, family members or health personnel, but cognitive test performance is in the normal range. In the general population, SCD is associated with an increased risk of future cognitive decline, that is, progression to MCI or dementia, including Alzheimer disease (AD). Relatively little is known about SCD in PD, and there are no established criteria for this syndrome. No reliable method of capturing SCD in PD yet exists, possibly owing partly to the confounding effects of motor symptoms and NMS. Nevertheless, SCD has been reported in patients with PD, and might be a harbinger of further cognitive decline in this population3.

MCI and the risk of PD dementia


The two most common cognitive syndromes in patients with PD, PDD and PD-MCI, were operationally defined in diagnostic and assessment guidelines from the International Parkinson and Movement Disorder Society (MDS)4,5. In PDD, but not in PD-MCI, the cognitive deficits are severe enough to impair daily life (for example, social and occupational functioning, and personal care), independently of the impairment ascribable to motor or autonomic symptoms.

Among PD patients without dementia, approximately 25–30% have MCI, which is evident at the time of diagnosis in 10–20% of patients2. Presence of MCI is associated with a shorter time to progression to a dementia diagnosis, although considerable variability is observed, with some patients remaining stable and some even reverting to normal cognition. For example, in one study of patients with early PD6, over 20% of those with MCI reverted to normal cognition after 1 year, although persistent MCI was associated with a much lower remission rate.

Early studies indicated that the mean time to dementia after PD diagnosis was approximately 10 years. This figure is supported by more recent studies, including some that monitored patients from the time of PD diagnosis (TABLE 1), which reported dementia prevalence of 15–20% after 5 years and 46% at 10 years7,8. However, lower dementia rates (5% after 4 years) have been reported elsewhere9. One study that selected only PD patients with normal cognition reported that nearly 50% had developed cognitive decline after 6 years10. Some studies11 suggest that cortical posterior cognitive deficits (that is, memory and language impairment), but not frontally based dysfunction, indicate a higher risk of dementia, leading to the ‘dual syndrome hypothesis’ of cognition in PD12. Discrepancies between studies are likely to be attributable to a variety of factors, including differences in case selection, whether duration was measured from onset of symptoms or diagnosis, use of different criteria for PD-MCI and PDD, and loss to follow-up.

Mechanisms

A variety of mechanisms, in addition to the classic nigrostriatal α-synuclein misfolding and dopaminergic neuronal loss, contribute to the brain changes associated with PD (BOX 1). PD is now recognized to involve multisystem, multipeptide neurodegeneration, with non-dopaminergic degeneration having a crucial role.

Mechanisms of cognitive decline

The following mechanisms are proposed to contribute to cognitive decline in Parkinson disease:

  • Protein misfolding (α-synuclein, amyloid and tau)
  • Neurotransmitter activity
  • Synaptic dysfunction and loss
  • Neuroinflammation and diabetes
  • Mitochondrial dysfunction and retrograde signalling
  • Microglial and astroglial changes
  • Genetics
  • Epigenetics
  • Adenosine receptor activation
  • Cerebral network disruption

Compared with the motor symptoms, little is known about the mechanisms underlying cognitive decline in PD, and several key questions remain unresolved. First, is cognitive decline merely a result of more severe and widespread involvement of primary PD neuropathophysiology? Second, are some of the PD-related mechanisms particularly relevant for cognitive decline? Last, is cognitive impairment related to regional involvement or specific mechanisms?

Information on the mechanisms underlying cognitive decline in PD has come from a variety of sources. In addition to postmortem studies, in vivo studies, including clinicopathological studies and biomarker studies involving electrophysiological, imaging, electrophysiology and biofluid analyses, and genetic studies, have all contributed to an increased understanding. However, animal models for PD-related cognitive deficits have been difficult to develop.

Evidence from pathological studies

The pathological contributions to dementia in PD have been studied in some detail, and have been reviewed elsewhere21. Good evidence from postmortem studies indicates that limbic and cortical Lewy body pathology is the main pathological correlate of dementia in PD. In most cases, α-synuclein pathology seems to spread from sites in the lower brainstem or olfactory bulb — or even extracranially from the gut or other areas innervated by the vagus nucleus1 — to the midbrain, forebrain and limbic structures and, finally, neocortical regions22.

Synaptic pathology and cognition

The structural pathologies described above are relevant, but only partially explain the variance in cognitive decline in patients with PD. A better understanding of the disease substrate is needed for targeted drug discovery and to enable better monitoring of disease progression. Changes in synaptic function followed by synaptic loss are likely to be early and key events in neurodegenerative diseases: in AD, loss of synapses was found to be more robustly correlated with cognitive decline than was morphological pathology27. Less is known regarding the role of synaptic dysfunction in cognition in PD, but synaptic alterations have been demonstrated (reviewed elsewhere28).

Neurotransmitters

Convincing evidence is available that mesolimbic and mesocortical dopaminergic activity is associated with cognitive functioning. The association between dopaminergic drugs and cognition is complex, however, and antiparkinson drugs can improve, worsen or have no influence on cognition35. In addition, a number of non-dopaminergic transmitter systems are affected in PD, and are likely to contribute to cognitive impairment21. For example, good evidence from postmortem and imaging studies indicates that the cholinergic system is affected relatively early in PD and contributes to the cognitive decline. Interestingly, whereas Lewy body and amyloid plaque pathologies were associated with earlier onset of dementia, cholinergic deficits were more pronounced in individuals with dementia occurring later in the disease course26,36. These observations provide a rationale for the positive effects of cholinesterase inhibitors in PD (see Management section below), as well as the worsening cognition associated with the use of medications with anticholinergic activity37.

Mitochondrial activity

Mitochondrial dysfunction occurs in PD, but little is known regarding its potential role in cognitive decline. However, mitochondrial pathology seems to contribute to cognitive decline in AD, and a recent postmortem study showed that deficiency in mitochondrial complex 1 activity and reduced mitochondrial DNA levels in the prefrontal cortex were more pronounced in PDD than in PD without dementia42.

Inflammation and neurotrophic factors

Neuroinflammation is relevant for both AD and PD, and might have important implications for cognitive decline in PD44, with a potential for novel treatment targets. Increased microglial activation is thought to lead to cell death in AD and PDD45, and inflammation markers represent possible prognostic biomarkers. Interestingly, CSF levels of cytokines are found to be associated with cognitive impairment in PD46 and, thus, represent possible biomarkers (see below).

Findings from many different sources convincingly demonstrate a link between diabetes, insulin resistance and PD, possibly via mechanisms involving neuro-inflammation and mitochondrial dysfunction47. A recent imaging study in a cohort of 36 patients, 12 of whom had diabetes, reported an association between diabetes, grey matter loss and cognitive impairment in PD48, indicating a possible role for antidiabetic drugs in the treatment or prevention of cognitive decline in PD, as has been suggested in AD.

Neurotrophic factors are crucial for neuronal plasticity and, thus, learning and other cognitive functions. A longitudinal study showed that cognitive impairment in PD was associated with reduced levels of growth factors, such as brain-derived neurotrophic factor and epidermal growth factor, in CSF49 and plasma50.

Summary

In addition to α-synuclein, tau and amyloid pathologies, a number of other mechanisms, including different neurotransmitter systems, early synaptic changes, inflammation, and mitochondrial dysfunction, are likely to contribute to cognitive decline in PD. The roles of these as well as other potentially relevant mechanisms for cognitive impairment, such as the unfolded protein response51, the ubiquitin–proteasome system52, and increased neurogenesis (for example, in response to neurotrophic factors)53, need to be explored further

Neuroimaging

Over the past decade, structural, functional and molecular neuroimaging techniques such as MRI106 and PET107109 have considerably advanced our understanding of the complex mechanisms underlying the development of cognitive impairment in PD106,109. Two large, ongoing 5-year observational biomarker studies, PPMI and COPPADIS, are using a range of imaging assessments, and are expected to yield important information on the utility of MRI to detect brain pathology in PD patients with cognitive impairment110. In such patients, PET imaging has provided in vivo evidence for the interplay between several pathological processes, including degeneration of subcortical cholinergic and dopaminergic projections, microglial activation, and neocortical pathology associated with misfolded protein deposition or vascular pathology45,107,111. Also, functional polymorphisms in the COMT gene, which influence dopamine storage, might contribute to cognitive deficits in PD112.

MRI measures of cortical and subcortical volume loss

Structural MRI can localize differences in regional cortical and subcortical tissue volume between groups of individuals. In PD patients without a formal diagnosis of PD-MCI or PDD, loss of tissue volume in frontal and parietal cortices has been associated with worse performance in decision-making, facial expression recognition, visual memory and executive function113115. Studies in patients with PD-MCI have demonstrated a pattern of cortical volume loss in posterior, parietal and frontal cortices, and atrophy in the hippocampus, that correlates with memory deficits116118. Longitudinal assessments of cortical thickness and subcortical volumes in patients with PD-MCI have indicated progression of cortical thinning in temporal, occipital, parietal and frontal cortices, and further loss of hippocampal volume that is associated with cognitive decline117,119.

Figure 1
Amyloid-β PET scans in Parkinson disease dementiaAxial slices from two patients with Parkinson disease dementia, showing a | absence and b | presence of amyloid-β binding. 11C-PiB, 11C-labelled Pittsburgh compound B.

Key points

  • The full spectrum of cognitive impairment, from subjective cognitive decline to dementia, has been observed in Parkinson disease (PD)
  • Mild cognitive impairment in PD usually progresses to dementia, but can be stable and even revert in some patients
  • The aetiology of cognitive impairment in PD has not been fully elucidated, but limbic and cortical Lewy body pathology seems to be the main cause
  • Amyloid plaque pathology also contributes to cognitive decline in PD, and amyloid pathology detected by cerebrospinal fluid analysis and imaging can predict subsequent dementia
  • Other probable mechanisms include genetics, synaptic pathology, neurotransmitter changes and inflammation
  • Cholinesterase inhibitors have symptomatic effects, but no disease-modifying treatments are available to reduce the risk of dementia in PD
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