Uncovering the Brain Changes Responsible for Cognitive Decline in PD

According to a new study, the cognitive difficulties experienced by some people with Parkinson’s disease (PD) may arise because of neuron loss in several regions of the brain. Using brain imaging, the study finds that the same brain changes that lead to movement symptoms in PD also contribute to mild cognitive problems. But different brain changes play a role in more severe cognitive symptoms in PD. The results were published online December 15 in JAMA Neurology.

For people with PD who experience cognitive difficulties, it is common to experience trouble with executive function, which refers to abilities such as paying attention, remembering details and finding words. Yet much like other symptoms of PD, the specific cognitive symptoms and their severity vary widely from person to person. For some, they are a minor annoyance, while for others, they significantly impair everyday life. In the more severe form, symptoms progress to dementia. 

Researchers know that movement symptoms of PD are caused primarily by the loss of dopamine neurons in a region of the brain called the substantia nigra, which communicate with neurons in the striatum, a brain region that controls movement. But the source of the PD cognitive symptoms in the brain is unclear. Researchers have suspected dopamine neurons of playing a role, as well as cholinergic neurons, which are linked to Alzheimer’s and other cognitive problems.

In the current study, researchers led by Nicolaas Bohnen, M.D., Ph.D., of the University of Michigan in Ann Arbor, used brain imaging to examine 143 people with PD, the majority of whom did not have dementia. Individuals were classified into five groups based on the severity of their cognitive symptoms in order to help correlate what the brain scans might reveal with their clinical symptoms.


  • Brain scans from all 143 participants with PD showed degeneration of the dopamine neurons from the substantia nigra to a part of the brain called the putamen. This degeneration is a hallmark brain change in PD, so it helped to confirm the participants’ PD diagnoses.
  • In about two thirds of the participants, it was relatively common to observe loss of dopamine neurons targeting a brain region adjacent to the putamen, called the caudate.   
  • Even though neuron loss of the caudate was common, only about half of people with minimal cognitive issues showed loss of neurons here. Thus, it did not seem strongly linked to mild cognitive impairment (MCI). However, among the most severely impaired cognitively, almost three-quarters had dopamine degeneration in the caudate. 
  • Only one third of people showed degeneration of cholinergic neurons in the cortex, the wrinkly, outermost layer of the brain.
  • Loss of cholinergic neurons was strongly linked with severe cognitive impairment as 86 percent of the most severely impaired also showed degeneration in that part of the brain.  Only 25 percent of people with mild cognitive impairment showed cholinergic degeneration in the cortex.
  • When the scientists looked to see who was missing both dopamine neurons in the caudate and cholinergic neurons in the cortex, they found almost three-quarters of the people with the greatest impairment indeed were missing both neuron types.  Rarely (about 15 percent of participants) did people have loss of both types yet have only minimal impairment.  
  • Statistical modeling suggests that the effect of losing both types of neurons was greater than would be expected from combining the effects of losing either separately.

What Does It Mean?

Cognitive difficulties are common in advanced stages of PD. The mechanisms leading to these cognitive changes are not well understood. In the current study the authors highlight the role of two pathways in the brain. First, they implicate the loss of dopamine neurons in the part of the brain called the caudate (cell loss in this pathway is quite common in PD, even among people who have only mild cognitive impairments).  Second, the authors also show evidence that cholinergic neurons in the cortex are important in the development of cognitive difficulties. 

Current FDA approved treatments for PD include medications that increase dopamine signals in the brain. Medications that increase cholinergic signals in the brain are also approved for the treatment of cognitive changes in PD, but their clinical effect is modest. Future research should focus on interventions and treatments that may spare these dopaminergic and cholinergic cells from the cell death that may occur in PD. 


Bohnen NI, Albin RL, Müller ML, Petrou M, Kotagal V, Koeppe RA, Scott PJ, Frey KA (2014) Frequency of Cholinergic and Caudate Nucleus Dopaminergic Deficits Across the Predemented Cognitive Spectrum of Parkinson Disease and Evidence of Interaction Effects. JAMA Neurology. December 15 DOI: 10.1001/jamaneurol.2014.2757 http://dx.doi.org/10.1001/jamaneurol.2014.2757 

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