Memory-related Mild Cognitive Impairment May Be Linked to More Severe Alpha-Synuclein Buildup, Researchers Say

Memory-related mild cognitive impairment in Parkinson’s disease may be associated with a more severe buildup of alpha-synuclein protein in the brain — such as that observed in more advanced stages of the disease, a study finds.

The results of the study, “Neuropathological Findings in Parkinson’s Disease With Mild Cognitive Impairment,” were published in Movement Disorders.

Studying neuropathological markers — meaning the molecular, cellular, or tissue abnormalities characteristic in a given disease — in people with neurological disorders like Parkinson’s allows doctors and scientists to better understand the different tissue changes that contribute to the disease mechanism of a given disorder.

Parkinson’s is a multisystem neurodegenerative disorder with motor and non-motor features caused by the selective death of midbrain dopamine-producing neurons. These nerve cells die because of the aggregation, or clumping together, of a protein called alpha-synuclein in structures commonly known as Lewy bodies. Alpha-synuclein is associated with the regulation of the release of dopamine, the neurotransmitter involved in controlling the start and stop of voluntary and involuntary movements.

Although cognitive impairment is one of the most common non-motor complications of Parkinson’s, not much is known about the molecular and brain abnormalities that characterize it. The studies that do exist indicate that Lewy body protein aggregates coexist with amyloid plaques, neurofibrillary tangles, and inflammation — all of which are also observed in Alzheimer’s disease.

To bridge this knowledge gap, a group of researchers now sought to determine the molecular, cellular, and tissue features that underlie Parkinson’s disease with mild cognitive impairment. The work was a collaboration between the Mayo Clinic in Arizona, the Barrow Neurological Institute, also in Arizona, the Banner Sun Health Research Institute in Arizona, the Cleveland Clinic in Ohio, and the University of California-Davis. The team used autopsy data from the Arizona Study of Aging and Neurodegenerative Disorders.

The scientists compared brain tissue abnormalities of people with amnestic mild cognitive impairment (MCI) with those of patients with non-amnestic MCI. Amnestic MCI is a type of mild cognitive impairment that primarily affects memory, while non-amnestic MCI affects thinking skills other than memory, including the ability to make decisions or visual perception.

Out of 736 screened individuals, 159 had pathologically defined Parkinson’s disease. Of these, only 25 — eight women and 17 men, ages 69-92 — had concurrent mild cognitive impairment. A total of 14 (56%) autopsied subjects had amnestic MCI while 11 (44%) had non-amnestic MCI.

The results revealed that each individual with Parkinson’s disease with mild cognitive impairment had significantly distinct molecular and tissue abnormalities from every other study subject with an identical diagnosis. Consequently, the scientists found no specific set of molecular, cellular, or tissue changes that they could reliably allocate to cognitive impairment in Parkinson’s.

Alpha-synuclein accumulation was more severe in some cases than others, and there were Alzheimer’s disease-related features — including neuritic plaques, neurodegeneration of cerebral white matter, and cerebral amyloid angiopathy, or amyloid buildup on the walls of brain arteries — in these patients’ brain samples. The scientists also observed that patients had a specific genetic variant of the apolipoprotein (APOE) gene, called APOE4, the most prevalent genetic risk factor for Alzheimer’s disease.

Importantly, non-amnestic patients had a significant increase in the severity of Lewy body pathology, or alpha-synuclein buildup, compared with amnestic subjects — 63% versus 21%.

The scientist note that there are apparently distinct biological mechanisms between Alzheimer’s and Parkinson’s disease. However, these neurodegenerative disorders seem to overlap to some extent.

While this is a relatively small study, the findings suggest that despite significant heterogeneity in cellular and tissue abnormalities, Parkinson’s patients with amnestic mild cognitive impairment might be more prone to greater alpha-synuclein accumulation.