By Rivka Sachdev, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medicine
SYNOPSIS: The features of gait difficulty, postural instability, and cognitive deficits in patients with Parkinson’s disease appear to be attributable to degeneration of cholinergic basal forebrain systems, including loss of fiber tract integrity and reduction of cortical projections.
SOURCE: Wu C, Wu H, Zhou C, et al. Cholinergic basal forebrain system degeneration underlies postural instability/gait difficulty and attention impairment in Parkinson’s disease. Eur J Neurol 2024;31:e16108.
Idiopathic Parkinson’s disease (IPD) has a complex presentation consisting of various motor and nonmotor symptoms. IPD often has been categorized into two main subtypes, the tremor dominant subtype (TD) and the postural instability/gait difficulty subtype (PIGD), although there is significant overlap between the two. Extensive literature exists about the PIGD subtype as having considerably more nonmotor symptoms, more deficits in balance and gait, faster rate of disease progression, higher risk of falls, and more cognitive impairment vs. the TD subtype. Often, however, tremor-dominant PD patients have a shift in subtype as the disease progresses and eventually most patients with PD experience some degree of gait difficulty, postural instability, and cognitive impairment as time goes on, progressively increasing the overall burden of disease.
Although supplemental levodopa significantly improves symptoms of tremor, rigidity, and bradykinesia in patients with PD, it does not provide patients with much, if any, improvement in postural instability or cognitive function. In fact, some dopaminergic treatments worsen cognition. A better understanding of the mechanisms that underlie gait/postural instability and cognitive impairment in PD is needed urgently so that better treatments can be developed for these particularly debilitating symptoms. The authors of this study bring us a step closer to understanding such mechanisms, highlighting the involvement of the cholinergic basal forebrain (cBF) system, including fiber tracts and cortical projections. They noted that cognitive function is fundamental to maintaining a balanced posture; diminished attentional capacity can increase the risk of falling. Cognitive impairment and PIGD appear closely related, and the authors suggested that the two may share a common pathophysiological deficit in the cholinergic system.
In this study, a total of 84 patients with PD and 82 normal controls were enrolled, after excluding anyone with cerebrovascular disease, history of head injury, presence of severe cerebral atrophy, history of neurosurgery, cognitive impairment with Mini-Mental State Exam (MMSE) score ≤ 24, treatment with anticholinergic medications, or use of choline-sterase inhibitors. No significant differences in age, gender, or years of education were observed between the two groups. All participants underwent motor and cognitive assessments. Motor symptom severity was assessed using scores from Part III of the United Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale. The PIGD score was calculated by summing select items from Parts II and III of the UPDRS. The cognitive assessments were done using the MMSE, Montreal Cognitive Assessment test, Boston Naming Test, Digit Span Test, Trail Making Test A, Auditory Verbal Learning Test, and Clock Drawing Test. For imaging, all participants underwent diffusion tensor imaging (DTI) to detect any structural abnormalities in the cBF. Segments of the cBF were traced using specialized tractography methods, and information regarding the extracellular water accumulation was obtained by quantifying the free water fraction. The free water fraction in the cBF and fiber tract, in addition to the cortical projection density, was extracted and statistically analyzed.
It was found that the PD patients showed cholinergic basal forebrain microstructural degeneration, reduced fiber tract integrity, and decreased cortical projections vs. controls. The cholinergic basal forebrain microstructural degeneration was significantly related to attention function, which mediated the association between cBF degeneration and severity of postural instability/gait difficulty. It also was found that PD patients had significantly higher free water fraction in the cBF and fiber tract (implying an increased amount of freely diffusing water molecules in the extracellular space caused by neuronal loss and neuroinflammation).
COMMENTARY
These findings may suggest that degeneration in the cholinergic basal forebrain system results in attentional impairment, which underlies postural and gait difficulty in PD. The authors concluded that postural instability/gait difficulty could be interpreted as “the outcome of cholinergic deficits within a framework of failing cognitive integration.”
These very important results are a key step for eventually improving management for gait dysfunction, postural instability, and cognitive impairment in our patients with PD. The cholinergic basal forebrain system plays a crucial role in attentional and motor integration. Treatment that uses cholinesterase inhibitors and cognitive training interventions should be further explored to improve postural and gait function in PD. Strategies for neuroprotection in PD should include efforts to slow down cholinergic system degeneration.
