Alzheimer disease (AD) is a common progressive neurodegenerative disease characterized by cognitive impairment and behavioral and functional decline. The deposition of intracellular “tangles” of hyperphosphorylated tau protein is one of the key pathologic hallmarks of the disease. Abnormal tau deposition begins within the basal forebrain before progressing to involve the neocortex via corticocortical axonal projections. The burden of tau pathology correlates well with the degree of neurodegeneration and cognitive impairment observed clinically.

The nucleus basalis of Meynert (NBM) is a basal forebrain nucleus which provides the majority of cortical cholinergic innervation. Neurons within the NBM are particularly susceptible to tau pathology, being affected more severely and at an earlier stage of the disease.¹ Neurodegeneration within the NBM results in cholinergic deficits, the key psychopharmacologic abnormality mediating clinically observed cognitive impairment. Cholinergic augmentation, with acetylcholinesterase inhibitors, remains one of the key treatment options in AD.

Assessment of the NBM in vivo therefore represents a novel precision medicine biomarker for the assessment of pathologic changes in patients with cognitive impairment.

The NBM can be identified on structural neuroimaging and stepwise volumetric reductions have been documented in individuals as they have progressed from normal to mild cognitive impairment (MCI) and AD.² Volumetric measurements are, however, not available routinely on radiology workstations. This study sought to determine whether NBM linear (thickness) measurements are altered across the aging-dementia spectrum and their clinical and biochemical correlates. This would represent a simplified and readily available tool for the assessment of subtle imaging changes in the cholinergic basal forebrain in patients with cognitive impairment.

In our study of patients from the Alzheimer’s Disease Neuroimaging Initiative dataset, we demonstrate progressive thinning of the NBM in patients with early and late MCI and AD compared with cognitively healthy controls. We show that NBM thickness measurements correlate with clinical measures of cognitive impairment (Alzheimer’s Disease Assessment Scale-Cognitive Subscale) and that this metric can be used to differentiate patients with AD and late MCI from cognitively healthy controls with excellent sensitivity. There is fair intrarater and good interrater observer reliability for measurements.

There is scope to improve visualization of the NBM, which is susceptible to artifacts at the base of the brain, which may improve measurement reliability. Our team has developed a novel imaging sequence to improve contrast resolution at the base of the brain using a phase-sensitive sequence.³ Measurement reliability was markedly improved in the pilot study using this novel sequence. Scan time of up to 6 minutes would also make this sequence clinically acceptable for use in patients.

Given the strategic importance of the NBM in the pathophysiology of AD, there is also scope for further research to assess whether NBM thickness can be used to predict disease trajectory, helping to differentiate individuals with stable MCI from those with progressive cognitive impairment. NBM thickness at baseline may also help predict response to treatment with cholinesterase inhibitors.

This research was undertaken at the University of Nottingham (Department of Radiological Sciences and Sir Peter Mansfield Imaging Centre) and has previously been presented at the European Congress of Neuropsychopharmacology (March 2018).

References

1. Liu AK, Chang RC, Pearce RK, et al. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s disease and Parkinson’s disease. Acta Neuropathol 2015;129:527–40.
2. Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 2012;71:805–13.
3. Jethwa K, Aphiwatthanasumet K, Mougin O, et al. Phase enhanced PSIR T1 weighted imaging improves contrast resolution of the nucleus basalis of Meynert at 7T: a preliminary study. Magn Reson Imaging 2019;61:296–99.

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