Aims

To assess the relationship between amyloid β (Aβ), substantia nigra (SN) atrophy, dopamine transporter (DAT) striatal activity, and white matter hyperintensities (WMH) and the risk of future freezing of gait (FOG) in de novo Parkinson’s disease (PD) patients.

Methods

We studied 423 participants from from the Parkinson’s Progression Markers Initiative (PPMI). Deformation based morphometry from anatomical MRI was used to measure SN atrophy. WMH load on MRI was used as a measure of white matter pathology. Cerebrospinal fluid (CSF) Aβ, putamen and caudate SPECT-based DAT levels were also obtained. Future FOG was evaluated using MDS-UPDRS items 2.13 and 3.11, defined as whether the score for either item was ≥ 1 at any follow-up visit. We investigated whether WMH burden mediates the impact of Aβ on future FOG, controlling for age, sex, SN atrophy, and DAT activity.

Results

Baseline SN atrophy, WMH load, Aβ, putamen and caudate DAT levels were significantly different between PD patients with and without future FOG (p < 0.008, Figure 1).

The effect of Aβ on future FOG was fully mediated via WMH burden, independent of either SN atrophy or DAT levels (average causal mediation effect: ab = - 0.013, p = 0.02; average direct effect: C' = -0.053, p = 0.053, Figure 2).

Conclusions

Baseline Aβ impacts future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology as measured by SN atrophy and striatal DAT activity.

Aims

To assess the relationship between amyloid β (Aβ), substantia nigra (SN) atrophy, dopamine transporter (DAT) striatal activity, and white matter hyperintensities (WMH) and the risk of future freezing of gait (FOG) in de novo Parkinson’s disease (PD) patients.

Methods

We studied 423 participants from from the Parkinson’s Progression Markers Initiative (PPMI). Deformation based morphometry from anatomical MRI was used to measure SN atrophy. WMH load on MRI was used as a measure of white matter pathology. Cerebrospinal fluid (CSF) Aβ, putamen and caudate SPECT-based DAT levels were also obtained. Future FOG was evaluated using MDS-UPDRS items 2.13 and 3.11, defined as whether the score for either item was ≥ 1 at any follow-up visit. We investigated whether WMH burden mediates the impact of Aβ on future FOG, controlling for age, sex, SN atrophy, and DAT activity.

Results

Baseline SN atrophy, WMH load, Aβ, putamen and caudate DAT levels were significantly different between PD patients with and without future FOG (p < 0.008, Figure 1).

The effect of Aβ on future FOG was fully mediated via WMH burden, independent of either SN atrophy or DAT levels (average causal mediation effect: ab = - 0.013, p = 0.02; average direct effect: C' = -0.053, p = 0.053, Figure 2).

Conclusions

Baseline Aβ impacts future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology as measured by SN atrophy and striatal DAT activity.