Elevated Beta-amyloid Levels Seen in Patients With Freezing of Gait
People with advanced Parkinson’s disease and freezing of gait (FOG) have higher levels of beta-amyloid — a protein that forms toxic clumps in the brains of those with Alzheimer’s disease — in their cerebrospinal fluid relative to patients without FOG, a small study reported.
The presence of FOG was also associated with significantly lower levels of fractalkine, an anti-inflammatory molecule, in the cerebrospinal fluid (CSF, the liquid that surrounds the brain and spinal cord).
Larger, longitudinal studies are needed to confirm these associations and clarify their clinical relevance, its researchers noted.
The study, “Cerebrospinal fluid biomarkers in Parkinson’s disease with freezing of gait: an exploratory analysis,” was published in the journal npj Parkinson’s Disease.
Freezing of gait, which is characterized by brief periods in which a person cannot start or continue walking, making them feel “glued” to the ground, often develops as Parkinson’s progresses. By arresting movement, FOG is “a leading cause of falls with injury, and results in loss of independence and social isolation,” the researchers wrote.
While FOG is known to be associated with longer disease duration and cognitive impairment, its root cause remains unclear and few studies have looked at potential CSF biomarkers of FOG.
A previous study showed that low CSF levels of a beta-amyloid fragment (Aβ42) in early Parkinson’s predicted FOG onset within the first years. Low Aβ42 levels in the CSF also is the first marker in predicting Alzheimer’s and its characteristic formation of toxic beta-amyloid clumps in the brain.
A team of researchers in the U.S. evaluated whether FOG in advanced Parkinson’s associated with CSF markers related to Alzheimer’s and inflammation.
Alzheimer’s-related markers included Aβ42, total tau, and phosphorylated tau (p-tau), while those related to inflammation included six pro-inflammatory molecules (TNF-alpha, IL-7, IL-8, TGF-alpha, IP-10, MCP-1) and four anti-inflammatory proteins (MDC, IL-9, IL-10, and fractalkine).
Of note, tau is a protein that forms toxic clumps in the brain of those with both Alzheimer’s and Parkinson’s.
The study involved 12 Parkinson’s patients with FOG (mean age, 70.7), 19 patients without FOG (mean age, 70.4), and 12 healthy adults as a control group (mean age, 74.4). The healthy group had a higher proportion of women (67%) than both FOG (37%) and non-FOG Parkinson’s groups (8%).
Parkinson’s duration (ranging from zero to 23 years) was not significantly different between groups (average of about 10 years), but patients with FOG had poorer cognitive function.
Results showed that, after adjusting for potential influencing factors, the levels of Aβ42, p-tau, and fractalkine were significantly different across groups.
Aβ42 levels were increased among patients with FOG relative to the other two groups, with healthy controls showing intermediate levels and patients without FOG showing the lowest.
Notably, Aβ42 levels in the CSF rose with greater disease duration in the FOG group, but showed an opposite trend among patients without FOG, suggesting that this increase is specific to Parkinson’s patients who develop FOG.
Data also suggested that FOG was linked to moderately reduced CSF Aβ42 levels in the first three years post-diagnosis — similar to previous studies — but associated with increased, rather than lower, levels after that point.
These results suggest that “the associations between lower CSF Aβ42 and incident FOG that hold in newly diagnosed PD patients may not generalize to older or more advanced patients,” the researchers wrote.
Parkinson’s patients, particularly those with FOG, also showed lower levels of the anti-inflammatory protein fractalkine compared with healthy controls. In addition, p-tau levels were reduced by about 40% in both Parkinson’s groups relative to healthy adults.
No associations between disease duration and fractalkine or p-tau levels were detected.
While p-tau level dynamics were consistent with previous studies, “the changes in Aβ42 and fractalkine were unexpected and in the opposite direction than those seen in comparisons of [Alzheimer’s patients] and [healthy controls],” the researchers wrote.
Future studies involving a larger number of patients and following them over time are needed to confirm these findings and better understand the underlying causes of these associations and their clinical relevance.
Such studies could help gain insight on whether “these changes are specific to FOG or relate to the cognitive change often associated with FOG or simply progression of disease,” the team wrote.
They could also help understand whether Parkinson’s patients with low CSF levels of Aβ42 represent a subset of patients with toxic beta-amyloid aggregates or altered amyloid metabolism in the brain, similar to what happens in Alzheimer’s.
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