Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease

Abstract

Objective: To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF.

Design: Matched case-control study.

Setting: The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research.

Patients: Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1-3) and 27 matched healthy control subjects.

Main outcome measures: We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes.

Results: Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls.

Conclusion: Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF.

Figure 1

Control subject. A and B, Representative axial (A) and sagittal (B) views of the midbrain of a control subject’s multispectral weighted mean. The red arrows in A and B indicate the substantia nigra. C, Shown are the substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), red nucleus (RN), and cerebral peduncles (CP). D, Example of the same control subject’s manually delimited label of the SNc (green).

Figure 2

Coronal images from a control subject showing the basal forebrain at the level of the anterior commissure. A, T2-weighted image. B, T2–fluid-attenuated inversion recovery (FLAIR) weighted image clearly demonstrates the improved contrast for both the superior and inferior boundaries in T2-FLAIR weighted images. The red arrows in A and B indicate the basal forebrain. C, T2-FLAIR weighted image with a manually delimited label of the basal forebrain (red).

Figure 3

The mean volumes of the substantia nigra pars compacta (A) and basal forebrain (B) for the left and right hemispheres. Shown are values for control subjects, patients with Hoehn and Yahr stage 1 Parkinson disease (H&Y 1), and patients with Hoehn and Yahr stages 2 and 3 Parkinson disease (H&Y 2–3). Bars are means (SEs). *Denotes P ≤ .05; † denotes P ≤ .10.

Figure 4

Multispectral weighted means showing the substantia nigra pars compacta (red arrows) in sagittal and axial views. A, Healthy young adult (21-year-old female). B, Healthy older control subject (69-year-old female). C, Age-matched and sex-matched patient with Hoehn and Yahr stage 2 Parkinson disease (H&Y 2) (69-year-old female). Signal loss is readily apparent in the Parkinson disease brain (yellow arrows).