Relationship Between Braak and Clinical Stage in Autopsy-Confirmed Parkinson Disease: A UK Brain Bank Study

The gold standard for Parkinson disease (PD) diagnosis is postmortem examination, based on the presence and distribution of pathologic α-synuclein (Lewy pathology) across brain regions. Whether pathologic α-synuclein Braak staging reflects clinical disease progression remains uncertain. We examined the relationship between Braak stage with clinical indices of PD progression in an autopsy-proven cohort.

We performed a retrospective clinicopathologic analysis of autopsy-confirmed PD cases from the Parkinson's UK Brain Bank (Imperial College London). Clinical records were systematically reviewed to extract age at symptom onset, disease duration, brain weight, Hoehn and Yahr (H&Y) stage at death, and key clinical features. Normality was assessed using Shapiro-Wilk tests; comparisons across Braak stages used Kruskal-Wallis tests. Correlations with Braak stage were examined using Spearman correlation with 95% CIs. Prevalence of major copathologies was summarized descriptively.

Of 119 clinically diagnosed PD cases, we included all 61 with autopsy confirmation and available Braak staging. Mean ± SD age at death was 79.1 ± 7.4 years, disease duration was 13.5 ± 5.8 years, H&Y stage at death was 4.0 ± 0.8, and brain weight was 1,234.2 ± 108 g. Braak stage was not correlated with H&Y at death (ρ = 0.146, 95% CI -0.11 to 0.39, p = 0.262), age at death (ρ = -0.210, 95% CI -0.47 to 0.07, p = 0.104), disease duration (ρ = 0.035, 95% CI -0.23 to 0.29, p = 0.787), or brain weight (ρ = 0.2, 95% CI -0.07 to 0.42, p = 0.139). There were no differences across Braak stages in disease duration (p = 0.925), age at death (p = 0.356), brain weight (p = 0.279), or H&Y stage (p = 0.603). By contrast, brain weight correlated negatively with age at death (ρ = -0.352, 95% CI -0.57 to -0.09, p = 0.005). Copathologies were common, including entorhinal/allocortical tau (B1-B2) in 82%, small vessel disease in 60%, β-amyloid (Thal ≥1) in 58%, and cerebral amyloid angiopathy in 25%. The prevalence of copathologies did not differ across Braak stages.

Braak stage was not associated with H&Y at death, disease duration, age at death, or brain weight in autopsy-proven PD patients. These findings provide evidence that pathologic α-synuclein-based staging does not represent a model of clinical progression in PD. The quantification of both monomeric and pathologic α-synuclein may be needed to overcome the clinical limitations of pathology-based staging.