In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease

Abstract

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.

Keywords: Parkinson’s disease; dementia; mild cognitive impairment; structural MRI.

Figure 1

Cholinergic basal forebrain regions of interest. Full details of how the subregional cBF map was generated can be found in Kilimann et al. (2014). The regions of interest have been superimposed on the T₁-weighted high-resolution ICBM 2009a Nonlinear Asymmetric MNI152 standard space template available at http://www.bic.mni.mcgill.ca/ServicesAtlases/ICBM152NLin2009. Slices from left to right are coronal slices −8, 3, 6, 9. Red represents the Ch1-2 region of interest corresponding to the medial septum and vertical limb of the diagonal band, green is the nucleus subputaminalis/anterior-lateral NBM and the horizontal limb of the diagonal band (not selected as an region of interest in the current paper), Light blue + dark blue represents the Ch4 region of interest corresponding to the NBM, and dark blue represents the Ch4p region of interest corresponding to the posterior NBM.

Figure 2

Box plot of cBF region of interest volumes at baseline in controls and Parkinson’s disease patients with and without suspected MCI. CBF region of interest volumes in controls, patients with Parkinson’s disease with and without suspected MCI, with the Ch4p region (corresponding to the posterior NBM) being significantly different between controls and Parkinson’s disease patients with suspected MCI.

Figure 3

Survival function for categorization as MCI or Parkinson’s disease dementia in cBF− and cBF+ patients. Cox proportional hazards survival functions for months between diagnosis of Parkinson’s disease and categorization as MCI or Parkinson’s disease dementia, separated by cBF− (green) versus cBF+ (blue) status for the Ch4 region (i.e. patients with Parkinson’s disease with reduced volumes in the NBM versus those with volumes within range of controls, respectively). PD = Parkinson’s disease; ROI = region of interest.

Figure 4

Linear growth curves in cBF− and cBF+ patients. Linear growth curves modelled in the cBF− versus cBF+ groups (patients with Parkinson’s disease with reduced volumes in the NBM versus those with volumes within range of controls, respectively). (A–D) A faster decline over 5 years on the MoCA, delayed and immediate recall on the HVLT, and semantic fluency.