Abstract
Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.
Highlights
Parkinson’s disease was often considered to be primarily a motor disorder dementia has long been recognized as a feature of the condition (Gowers, 1893)
We have proposed two facets of cognitive deficits in Parkinson’s disease, in a ‘Dual Syndrome’ hypothesis: (i) changes in dopaminergic transmission through the corticostriatal networks leading to deficits in planning, working memory, response inhibition and attentional control; and (ii) posterior cortical Lewy body pathology and secondary cholinergic loss affecting visuospatial, mnemonic and semantic functions (Kehagia et al, 2013)
Exclusion criteria were: parkinsonism diagnosed before the onset of the incidence study; insufficient working knowledge of English to perform the neuropsychological assessment; dementia at presentation [defined as Mini-Mental State Examination (MMSE) score 5 24 or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria for dementia or Movement Disorder Society criteria for dementia]; lack of mental capacity to give informed consent under UK legislation; history of parkinsonism following the onset of cognitive impairment; history or examination suggestive of dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, repeated strokes or stepwise progression of symptoms indicative of ‘vascular parkinsonism’; and, exposure to dopamine receptor blocking agents at the onset of symptoms
Summary
Parkinson’s disease was often considered to be primarily a motor disorder dementia has long been recognized as a feature of the condition (Gowers, 1893). The cognitive deficits of Parkinson’s disease affect visuospatial, attentional, executive and memory functions (Janvin et al, 2006; Hely et al, 2008; Elgh et al, 2009; Aarsland and Kurz, 2010; Pedersen et al, 2013) due to the combination of abnormal neurotransmitter systems (e.g. dopaminergic and cholinergic) and both cortical and subcortical Lewy body pathology (Kehagia et al, 2010). We have proposed two facets of cognitive deficits in Parkinson’s disease, in a ‘Dual Syndrome’ hypothesis: (i) changes in dopaminergic transmission through the corticostriatal networks leading to deficits in planning, working memory, response inhibition and attentional control; and (ii) posterior cortical Lewy body pathology and secondary cholinergic loss affecting visuospatial, mnemonic and semantic functions (Kehagia et al, 2013). It is important to ascertain what determines cognitive decline, and how it relates to subsequent dementia
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