Although predominantly considered a movement disorder, 30 to 70% of Parkinson's disease (PD) patients will develop associated dementia (PDD) and approximately 3 to 4% of all dementia is a result of PDD.1,2
PDD typically involves primary deficits in executive and visuo-spatial functions with secondary impairments in memory,3
resulting in significant reduction in quality of life.4
Pathologically, PD is characterized by protein aggregates, called Lewy bodies, in dopaminergic neurons of the substantia nigra. These Lewy bodies are composed of ubiquitinated α-synuclein and other proteins.5
PDD is associated with the spread of this Lewy body pathology into limbic and cortical areas.6-8
Although Alzheimer's disease (AD) pathology and Lewy body pathology frequently overlap in PDD, Lewy body pathology is associated with the dysexecutive and visuo-spatial dysfunction of PDD.9,10
In cortical layers V and VI, pyramidal neurons are particularly susceptible to Lewy body formation and cell death. Aggregation of proteins into LBs may injure neuronal cells, perhaps contributing to neurodegeneration11-14
; but, it is unclear which factors contribute to cortical neurode-generation in PDD. Interestingly, a large family with identified α-synuclein locus triplication15
exhibits a clinical phenotype with high probability of dementia16
and has extensive cortical LBs and some glial cell cytoplasmic inclusions. However, aside from a handful of instances of LRRK2 mutations, none of the genes responsible for familial forms of PD have been shown to be mutated in the sporadic form of the disease, which constitutes >95% of individuals suffering from PD.
Numerous gene expression microarray studies have examined differential gene expression in the midbrain of PD patients. These studies have identified the altered expression of genes related to oxidative stress, inflammatory responses, protein degradation, vesicle trafficking, and protein chaperone functions.17,20
More recently, single cell profiling of dopaminergic neurons using laser capture microdissection identified alterations in signaling pathways, in genes involved in neuronal maturation, and in several protein kinases in the substantia nigra pars compacta (SNc) of PD patients.21
To date, there is no comprehensive study looking at gene expression in vulnerable cortical neurons of patients with PDD.
To probe the underlying molecular factors that contribute to cortical neurodegeneration in PDD, we have used laser-capture microdissection to isolate layer V-VI pyramidal neurons from the posterior cingulate cortex of 14 healthy control individuals, 15 cognitively normal PD patients (PD-CogNL), and 13 patients with PDD. We identify substantial alterations in cortical neuronal gene expression in PDD relative to either PD-CogNL or healthy controls, consistent with the onset of cortical pathology characteristic of PDD. In contrast, relatively few cortical genes are affected in PD-CogNL when compared with healthy controls. However, those genes that are dysregulated in PD-CogNL patients may provide insights into the underlying initiating events that lead to the subsequent development of dementia.