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Higher White Matter Hyperintensity Associated With Faster Parkinsonism Progression

The association between white matter hyperintensity remained significant even after controlling for vascular risk factors and diseases.

A recently conducted study published in JAMA Neurology examining decedents that were without a diagnosis of Parkinson disease (PD) showed that higher levels of white matter hyperintensity (WMH) were associated with more rapid progressive parkinsonism.

The community-based cohort study led by Shahram Oveisgharan, MD, assistant professor, Rush Alzheimer’s Disease Center, Rush University, examined the associations between WMH burden and the rate of progressive parkinsonism. A Fazekas rating scale was used to assess WMH burden while parkinsonism was assessed annually using 26 items of a modified motor portion of the Unified Parkinson’s Disease Rating Scale (UPDRS).

Patients were recruited from 3 ongoing longitudinal studies that began enrollment in 1994, 1997, and 2004. Over that time, 2134 of the 4427 enrolled patients died, with postmortem autopsy conducted for 1725 of the decedents. For this analysis, 516 decedents were included, with a mean age at death of 90.2 years (standard deviation [SD], 6.4]) and 364 (70.5%) individuals being female.

In total, 47.3% (n = 244) had severe WMH burden, 35.1% (n = 181), and 17.6% (n= 91) had no to mild levels of WMH. Annual examinations for a mean of 7.5 years (SD, 4.1) showed an increased severity in root-transformed parkinsonism score from 2.8 (SD, 1.2; range, 0-7.6) at study baseline to 3.8 (SD, 1.3; range, 0-7.4) proximate at death.

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After controlling for demographic characteristics, a linear mixed-effects models also reported an increase in severity of parkinsonism by about 0.13 units per year (estimate, 0.128 [standard error (SE), 0.007]; P <.001), with higher levels of WMH associated with more rapid progressive parkinsonism (estimate, 0.024 [SE, 0.008]; P = .002). Additionally, more severe WMH was associated with more severe parkinsonism proximate at death (estimate, 0.325 [SE, 0.076]; P <.001).

A separate model-derived estimate comparing the rate of progressive parkinsonism in 2, 90-year-old women with average education but different burdens of WMH showed a 51% faster rate of progressive parkinsonism for the women with severe WMH compared to the other, who had a mild case. Additionally, the association of WMH with parkinsonism remained significant when controlling for vascular risk factors and diseases.

"These longitudinal findings support a notion that both WMH and cerebrovascular disease pathologies may be underestimated independent contributors to progressive parkinsonism, which is common in older adults," Oveisgharan et al wrote. "Prospective studies are needed to determine if in vivo brain imaging for signs of WMH and more aggressive medical treatment of vascular risk factors and diseases in older adults may reduce the common occurrence of progressive parkinsonism in aging adults."

In addition to progressive parkinsonism, higher level of WMH was associated with more rapid progression of bradykinesia (estimate, 0.036 [SE, 0.012]; P = .004) and parkinsonian gait (estimate, 0.036 [SE, 0.012]; P =.003). Furthermore, a higher chance of rigidity (OR, 1.75 [95% CI, 1.30-2.36]; P <.001) was also associated with these high levels; however, the same was not observed for tremor (OR, 0.97 [95% CI, 0.75-1.26]; P = .82).

Previous research has indicated that more rapid progression is associated with a higher burden of PD and cerebrovascular disease pathology, this current analysis showed that WMH is associated with postmortem brain pathologies. In an attempt to understand the independent association between WMH and progressive parkinsonism, adding terms for cerebrovascular disease pathologies attenuated the association by 21% (without cerebrovascular disease pathologies: estimate, 0.024 [SE, 0.008; P = .002]; controlling for pathologies: estimate, 0.019 [SE, 0.008; P = .02]).

When adding terms for neurodegenerative pathologies, including PD pathology, the association of WMH with progressive parkinsonism was attenuated by 8% (controlling for neurodegenerative pathologies: estimate, 0.022; SE, 0.008; P = .003). The study authors wrote, "these findings indicate that WMH has an association with progressive parkinsonism apart from markers of both neurodegenerative and other cerebrovascular disease pathologies measured in the current study."

Oveisgharan S, Yu L, Poole V, et al. Association of white matter hyperintensities with pathology and progression of parkinsonism in aging. JAMA Neurol. Published online November 1, 2021. doi:10.1001/jamaneurol.2021.3996