Abstract
Dementia is a common and devastating symptom of Parkinson's disease but the anatomical substrate remains unclear. Some evidence points towards hippocampal involvement but neuroimaging abnormalities have been reported throughout the brain and are largely inconsistent across studies. Here, we test whether these disparate neuroimaging findings for Parkinson's disease dementia localize to a common brain network. We used a literature search to identify studies reporting neuroimaging correlates of Parkinson's dementia (11 studies, 385 patients). We restricted our search to studies of brain atrophy and hypometabolism that compared Parkinson's patients with dementia to those without cognitive involvement. We used a standard coordinate-based activation likelihood estimation meta-analysis to assess for consistency in the neuroimaging findings. We then used a new approach, coordinate-based network mapping, to test whether neuroimaging findings localized to a common brain network. This approach uses resting-state functional connectivity from a large cohort of normative subjects (n = 1000) to identify the network of regions connected to a reported neuroimaging coordinate. Activation likelihood estimation meta-analysis failed to identify any brain regions consistently associated with Parkinson's dementia, showing major heterogeneity across studies. In contrast, coordinate-based network mapping found that these heterogeneous neuroimaging findings localized to a specific brain network centred on the hippocampus. Next, we tested whether this network showed symptom specificity and stage specificity by performing two further analyses. We tested symptom specificity by examining studies of Parkinson's hallucinations (9 studies, 402 patients) that are frequently co-morbid with Parkinson's dementia. We tested for stage specificity by using studies of mild cognitive impairment in Parkinson's disease (15 studies, 844 patients). Coordinate-based network mapping revealed that correlates of visual hallucinations fell within a network centred on bilateral lateral geniculate nucleus and correlates of mild cognitive impairment in Parkinson's disease fell within a network centred on posterior default mode network. In both cases, the identified networks were distinct from the hippocampal network of Parkinson's dementia. Our results link heterogeneous neuroimaging findings in Parkinson's dementia to a common network centred on the hippocampus. This finding was symptom and stage-specific, with implications for understanding Parkinson's dementia and heterogeneity of neuroimaging findings in general.
Highlights
Dementia is a common and debilitating aspect of Parkinson’s disease: 50% of patients will develop dementia within 10 years of diagnosis (Williams-Gray et al, 2013), and it carries significant societal and economic burden (Spottke et al, 2005; Leroi et al, 2012) with high levels of frailty and nursing home admissions (Fredericks et al, 2017; Weir et al, 2018)
The meta-analyses included only articles that (i) involved patients with Parkinson’s disease and dementia, with PD dementia defined as a dementia syndrome that developed in the context of established Parkinson’s disease (Emre et al, 2007); (ii) reported coordinates for atrophy or hypometabolism (FDG-PET or single photon emission computed tomography (SPECT)) between the relevant patient groups; (iii) used comparisons between the symptom in question and Parkinson’s patients without that symptom; (iv) reported whole-brain results for these changes; (v) coordinates were reported in stereotactic space (montreal neurological institute (MNI) or Talairach)
We show that neuroimaging findings in Parkinson’s dementia are heterogeneous across different studies, but are 10 | BRAIN COMMUNICATIONS 2019: Page 10 of 17
Summary
Dementia is a common and debilitating aspect of Parkinson’s disease: 50% of patients will develop dementia within 10 years of diagnosis (Williams-Gray et al, 2013), and it carries significant societal and economic burden (Spottke et al, 2005; Leroi et al, 2012) with high levels of frailty and nursing home admissions (Fredericks et al, 2017; Weir et al, 2018). Identifying the neuroanatomical substrate of Parkinson’s disease with dementia (PD dementia) could aid prognosis and treatment development. Memory problems are frequently the first subjective cognitive complaint in Parkinson’s disease (Noe et al, 2004) and are a prominent component of PD dementia (Whittington et al, 2000; Bronnick et al, 2007; Muslimovic et al, 2007; Reid et al, 2011; Wang et al, 2015), forming part of the diagnostic criteria for PD dementia (Emre et al, 2007). In patients with PD dementia the hippocampus shows a higher density of Lewy pathology (Harding and Halliday, 2001; Apaydin et al, 2002; Arnold et al, 2013; Hall et al, 2014), reduction in cholinergic activity (Hall et al, 2014) and progressive atrophy with disease progression (Aybek et al, 2009; Weintraub et al, 2011, 2012; Morales et al, 2013; Kandiah et al, 2014; Mak et al, 2015; Gee et al, 2017; Mihaescu et al, 2018)
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