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 (Qalb), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative copathology. 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; I-2 = 92.2%) and in PDD/DLB (N-PDD/DLB/N-HC = 265/ 670; SMD = 1.126 [0.358-1.893], p < 0.001; I-2 = 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; I-2 = 91.9%) and PDD/DLB (N-PDD/DLB/N-HC = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I-2 = 92.7%) than in HC. p-tau 181 (N-PD/N-HC = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I-2 = 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; I-2 = 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. Qalb (N-PDD/N-PDND = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I-2 <0.001%) and NfL (N-PDD/N-PDND = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I-2 = 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.