Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases: A systematic review and meta-analysis

Background: Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases.

Methods: We compare biofluid markers in people with idiopathic Parkinson's disease (PD) and people with PD dementia (PDD) and/or dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Q_alb), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative co-pathology. We further explore differences between PD patients with and without evidence of dementia. Random-effects models were used to obtain standardized mean differences (SMD) with 95% confidence interval.

Results: Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Q_alb was higher in PD (N_PD/N_HC = 224/563; SMD = 0.960 [0.227-1.694], p = 0.010; I² = 92.2%) and in PDD/DLB (N_PDD/DLB/N_HC = 265/670; SMD = 1.126 [0.358-1.893], p < 0.001; I² = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (N_PD/N_HC = 1848/1130; SMD = 0.747 [0.442-1.052], p < 0.001; I² = 91.9%) and PDD/DLB (N_PDD/DLB/N_HC = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I² = 92.7%) than in HC. p-tau 181 (N_PD/N_HC = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I² = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (N_PDND/N_HC = 1005/740; SMD = 0.252 [0.042-0.462], p = 0.018; I² = 71.8%) and higher in PDD (N_PDD/N_HC = 100/111; SMD = 0.780 [0.347-1.214], p < 0.001; I² = 46.7%) compared to HC. Q_alb (N_PDD/N_PDND = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I²<0.001%) and NfL (N_PDD/N_PDND = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I² = 3.4%) were higher in PDD than in PD without dementia.

Conclusions: Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.