Kininogen-1 Protein Linked to Early Cognitive Impairment in Parkinson’s

People with Parkinson’s disease who have higher levels of the protein kininogen-1 in the fluid surrounding their brains and spinal cord are more likely to experience early cognitive impairment, a new study suggests.

The study, “Cerebrospinal Fluid Levels of Kininogen‐1 Indicate Early Cognitive Impairment in Parkinson’s Disease,” was published in Movement Disorders.

Cognitive impairment is a common non-motor symptom of Parkinson’s disease. An ongoing area of Parkinson’s research is the search for biomarkers that can provide prognostic information about cognitive impairment and other symptoms.

In the new study, researchers looked for biomarkers associated with cognitive function in 69 people with idiopathic (non-familial) Parkinson’s who participated in the AETIONOMY project. Specifically, the researchers measured levels of 216 proteins in the participants’ cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord.

Cognitive function was primarily assessed using the Repeatable Battery for the Assessment of the Neuropsychological Status (RBANS). In particular, a score of 90 or above was considered high (indicating better cognition), whereas a score below 90 was considered low — 90 was chosen as the cutoff because it is the threshold for average performance on this test.

Two other validated measures of cognition, the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), were also used.

Of the 69 people assessed, 34 had high RBANS total scores, and the remaining 35 had low scores. The two groups were similar in terms of age at diagnosis, disease duration, sex, lifestyle habits, and reported symptoms.

In initial statistical analyses, the researchers identified three proteins that were present at significantly higher levels in the CSF of those with low scores: kininogen-1 (KNG1), a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), and kallikrein‐6 (KLK6).

In subsequent analyses, which made statistical adjustments for possible confounding factors, KNG1 was significantly predictive of the RBANS score — that is, individuals with high KNG1 levels in their CSF were statistically more likely to have low RBANS scores. The other two proteins were not significantly associated with the RBANS score in these models.

The researchers calculated the area under the ROC curve (AUC) for KNG1 as a predictor of RBANS scores. This is a type of statistical analysis that essentially tests whether a given factor (in this case, KNG1 level) can be used to discriminate between two groups (high or low RBANS scores). AUC values can range from as low as 0.5 (no discriminatory power) to 1 (perfect discrimination). The calculated AUC for KNG1, as a predictor of RBANS score, was 0.8.

KNG1 was also significantly associated with MoCA scores, but not with MMSE scores. The researchers postulated that this may be attributable to differences in these cognitive measures: “Previous studies have shown that MoCA has more adequate psychometric properties than MMSE for detection of [Parkinson’s disease]‐related mild cognitive impairment or dementia,” they wrote.

“In our study, CSF levels of KNG1 were associated with cognitive performance of PD [Parkinson’s disease] patients without overt dementia,” the researchers concluded. “Increased CSF levels of KNG1 were associated with low RBANS and MoCA total score in PD patients, independent of sex, disease duration, and potential confounders including anxiety and hyposmia [decreased sense of smell].”

The protein KNG1 plays roles in regulating coagulation (blood clotting) as well as inflammation. Prior to this study, it had not been associated with Parkinson’s. However, some previous research has suggested the protein may play a role in another cognitive disorder: Alzheimer’s disease.

It’s not entirely clear whether or not the new findings match up with this previous research, though, because the KNG1 protein can be present in either a cleaved or intact form. The cleaved form has been implicated in Alzheimer’s but, in this study, the assay the researchers used did not distinguish between the two forms.

“Our findings may be in line with previous [Alzheimer’s] research, assuming that higher levels of KNG1 in our patients with lower cognitive scores reflect cleaved KNG1, but further studies with assays that distinguish between intact and cleaved KNG1 are needed,” the researchers wrote.

Limitations of the study included the relatively small sample size, and the fact that no individuals with late‐stage disease were included in the analysis. Further research is needed to better understand the role of KNG1 in Parkinson’s, the researchers wrote.

“Longitudinal studies with serial cognitive assessments and lumbar punctures are necessary to further explore the nature of KNG1 levels to detect cognitive decline and predict dementia development,” they said.