MRI to Visualize Progression in Parkinson’s Disease

Abstract & Commentary

By Claire Henchcliffe, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmith-Kline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidepoint Global.

Synopsis: This case-control study uses multi-spectral structural MRI sequences to examine two areas of tissue volume loss at different stages of Parkinson’s disease (PD). Data support involvement of the substantia nigra at earlier stages of PD than basal forebrain.

Source: Ziegler DA, et al. Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease. Arch Neurol 2012; Nov 26:1-7 [Epub ahead of print].

The investigators aimed to determine whether substantia nigra pars compacta (SNc) degeneration occurs earlier in Parkinson’s disease (PD) than basal forebrain (BF) degeneration, as predicted by the influential “Braak hypothesis” that proposes a characteristic pattern of temporal progression of PD pathology. Participants included 29 subjects with PD, with mean age 65.3 (± 8.8) years, mean Mini Mental Status scores of 28/30 (± 1.6), with more right- than left-sided symptom onset. Subjects were divided into groups comprising PD Hoehn and Yahr (H&Y) stage 1 (unilateral symptoms), and H&Y stages 2 + 3 (bilateral symptoms, with or without postural instability, independently ambulating). Those in H&Y stage 1 had shorter disease duration (3.1 ± 1.4 years) and lower impairment judged by the Unified Parkinson’s Disease Rating Scale (UPDRS) (9.2 ± 5.4 points) compared with H&Y stages 2 + 3 (4.8 ± 2.9 years’ duration, 19.7 +/- 8.3 UPDRS points), although only the difference in UPDRS points met statistical significance. A group of 27 healthy control subjects were matched for age, gender, and years of education. All participants underwent MRI scans using a 3 Tesla magnet, and high-resolution multispectral data included multi-echo magnetization-prepared rapid gradient echo with T1 weighting, 3-dimensional (3D) T2-weighted turbo-spin echo, multi-echo fast low angle shot with proton density weighting, and 3D T2-weighted FLAIR turbo-spin echo sequences. In PD H&Y stage 1, the left SNc was smaller than in controls (P = 0.001; right side not significant). For those with PD H&Y stages 2 + 3, both left and right SNc volumes were significantly smaller than controls but not PD H&Y stage 1. In contrast, BF volumes in subjects with PD H&Y stage 1 were not significantly different from controls, but those with PD H&Y stages 2 + 3 had significantly reduced BF volume vs controls (left: P = 0.008; right: P = 0.01), and PD H&Y stage 1 (P = 0.04 on the left side; right side not significant).

Commentary

Current understanding of the spread of PD pathology postulates that alpha-synuclein pathology, reflected by Lewy bodies and Lewy neurites, begins in the peripheral autonomic nervous system, and then involves the central nervous system, specifically, the olfactory bulb and medulla early on, progressing rostrally to involve the basal forebrain cortex. This neuropathologic pattern reflects the clinical motor findings and non-motor features such as constipation and olfactory dysfunction, which may appear years before motor symptoms. This pattern also explains the cognitive decline related to cortical involvement later in the disease. However, it has been difficult to directly confirm this pattern of spread due to limited biomarkers of regional neuronal loss. The authors chose two critical structures: the dopaminergic SNc, responsible for the vast majority of motor dysfunction in PD, and the cholinergic BF, associated with developing cognitive decline in PD. According to the Braak hypothesis, SNc is affected prior to BF involvement. The finding that SNc volume is measurably decreased in PD at both early and later stages, and that BF volume loss is only significant in later stages, certainly is consistent with the Braak hypothesis, and makes clinical sense. However, just as Braak’s study examining patterns of alpha-synuclein pathology only tells a part of the story, so it is with MRI. The Braak hypothesis does not address neurotransmitter changes that might occur prior to alpha-synuclein pathology. MRI likewise is unable to measure these changes. Previous studies support loss of cholinergic forebrain neurons in early PD, and it would be helpful to correlate volumetric MRI and nuclear imaging of specific neurotransmitters. Moreover, a longitudinal study will be extremely important. Despite this, the investigators demonstrate that the days of using MRI simply to rule out other processes may soon be over. Other studies have demonstrated cortical thinning, especially frontotemporal, global gray matter and amygdala atrophy, and decrease in olfactory bulb volume (although this last is not in all studies) in PD. The sophisticated multispectral MRI techniques that the investigators have developed now make possible the types of studies being undertaken in other neurodegenerative disorders such as Alzheimer’s and Huntington’s disease. Finally, not only does this approach advance understanding PD progression as a whole, it will be invaluable in monitoring differences between individuals.