This scientific commentary refers to ‘Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer’s disease’, by Richter et al. (doi:10.1093/brain/awx356). The cholinergic neurotransmitter system has long been known to play an important role in the cognitive decline of Alzheimer’s disease and, more broadly, in the memory deficits that occur with age and across neurodegenerative disorders. In the 1970s, autopsy studies revealed marked loss of cholinergic enzymes in the cortex and cholinergic cell loss in the basal forebrain, particularly in those subregions that project to Alzheimer’s disease-affected cortex. These findings, together with the known cholinergic contribution to memory and other cognitive skills, led to the ‘cholinergic hypothesis’ of Alzheimer’s disease. Subsequently, other pathologies such as amyloid-β proteinopathy, neurofibrillary tangles, and neuroinflammation have been considered the hallmarks of the disease. Recent research, however, indicates that alterations in the cholinergic neurotransmitter system are probably more than a historical footnote. There are known interactions among Alzheimer’s disease pathologies that include the cholinergic system: amyloid-β can be toxic to cholinergic receptors and, conversely, nicotinic cholinergic receptor stimulation can inhibit amyloid-β production and phosphorylated tau accumulation (Ovsepian et al., 2016). Within the cholinergic system, basal forebrain cell loss or local tau accumulation occurs very early in the Alzheimer’s disease process (Mesulam, 2013), is associated with cortical amyloid deposition (Grothe et al., 2014), and precedes and predicts entorhinal volume loss and memory impairment (Schmitz et al., 2016). In healthy older adults, basal forebrain volume is associated with general cognition, and the integrity of this structure may contribute to brain resiliency in ageing and resistance to cognitive decline in Alzheimer’s disease (Wolf et al., 2014). With regard to downstream cortical receptors, nicotinic cholinergic receptor availability declines with healthy ageing and more substantially in mild cognitive impairment (MCI) and early Alzheimer’s disease, in association with memory deficits and at least partly independent of hippocampal volume, suggesting a primary role in cognitive decline (Sultzer et al., 2017). In the current issue of Brain, Richter and co-workers take an important next step to better define cholinergic system function in those with MCI at risk for Alzheimer’s disease, and the related treatment implications (Richter et al., 2018). The work by Richter et al. evaluates relationships among cortical acetylcholinesterase enzyme activity, task-related neural system activation, and memory in MCI, both before and after acute treatment with cholinesterase inhibitor medication. The study’s hypotheses recognize that the clinical benefit of currently available pro-cholinergic medications varies considerably in Alzheimer’s disease and, on average, is not robust. Moreover, while there is evidence of cholinergic system dysfunction in normal ageing and MCI, pro-cholinergic treatments in MCI have not generally been shown to be effective. Richter et al. speculate that the clinical benefit of cholinergic treatment may depend on the presence of regional cholinergic dysfunction, which may not be sufficiently advanced at the MCI stage. Thus, they measured the effect of cholinergic treatment on neural system activation in both healthy elderly and those with MCI. The investigators also measured cortical cholinesterase activity and its impact on task-related cortical activation in the same model. The approach taken by the investigators to address these questions has several distinct strengths. First, the MCI sample met clinical diagnostic criteria, but in addition had CSF biomarker evidence of the Alzheimer’s disease process as well as evidence of neuronal degeneration. Prior work indicates that this sample is highly likely to have an amyloid-based disorder consistent with Alzheimer’s disease. The sample is well-characterized and more homogeneous than usual clinical MCI samples. Second, the study employed several neuroimaging tools to assess brain structure, function, and a cholinergic marker in each participant. Structural MRI measured volume of the hippocampus, which aids memory encoding and is atrophic in Alzheimer’s disease. Functional MRI measured the response of integrated neural activity to a memory-encoding stimulus. 11C-N-methyl-4-piperidyl acetate (MP4A) PET imaging assessed regional cortical activity of acetylcholinesterase enzyme, a proxy for local cholinergic neurotransmitter input and potentially linked to the structural integrity of cholinergic neuronal tracts and the basal forebrain region. These neuroimaging measures together with clinical cognitive measures provide an opportunity to systematically evaluate inter-relationships among the biomarkers and clinical state. Of particular value, the functional MRI assessment of neural responsivity to a memory task was performed both before and after acute treatment with rivastigmine, a cholinesterase inhibitor medication. This strategy serves as an intervention to acutely perturb acetylcholine-responsive neural systems, testing for change in brain measures or change in relationships among brain measures in response to enhanced acetylcholine availability. Collectively, this method evaluates simultaneously a host of factors that link baseline cholinergic system function to brain activity at different levels of acetylcholine availability in both healthy and pre-Alzheimer’s disease adults. The results showed that cortical cholinesterase enzyme activity was lower in the MCI group compared to the cognitively healthy group in predominantly lateral temporal and posterior cortex, with reductions also noted in medial temporal and frontal cortex (Fig. 1 in Richter et al.). Functional MRI revealed lower temporal cortex activation and posterior cingulate deactivation in response to a memory task in the MCI group compared to healthy elderly (Fig. 3 in Richter et al.). With acute rivastigmine treatment, the temporal activation and posterior cingulate deactivation increased in the MCI group, suggesting ‘normalization’ towards the healthy group. In contrast, with rivastigmine treatment, the activation pattern in the healthy group shifted towards that seen in the untreated MCI group. The extent of these rivastigmine-induced activation changes was inversely associated with local cholinesterase enzyme activity on MP4A imaging in the combined group, indicating that the brain activation normalization that occurs in MCI with acute pro-cholinergic treatment is dependent on a baseline cortical cholinergic deficit. The study also found that clinical benefit — memory improvement — with acute rivastigmine treatment in the MCI group depended on a local cortical cholinergic deficit. Moreover, this effect was not accounted for by hippocampal atrophy, suggesting that both local cholinergic activity and hippocampal structural volume independently contribute to memory change with pro-cholinergic intervention. Collectively, these findings provide a view of how brain structure, the cholinergic neurotransmitter system, and neuronal network responsivity work together during a memory encoding task. The effect of pro-cholinergic intervention on these functional measures and their dependence on local cholinergic activity is apparent. These are important steps forward. Some caution is warranted, however, in interpreting the findings. The implications rest on assumptions that the neuroimaging measures are true proxies for specific underlying biologies. For example, MP4A PET imaging measures only one aspect of the brain’s ‘cholinergic state’. In addition, the rivastigmine challenge was a single dose and consequences of enduring treatment may differ. Interestingly, whether the observed findings in MCI represent a pathology-driven steady decline towards clinical Alzheimer’s disease versus a compensatory response by the brain to address emerging Alzheimer’s disease pathology remains unclear. Nonetheless, the findings are important, expand the knowledge base for how the at-risk Alzheimer’s disease brain works, and indicate that the cholinergic system, via direct neurotransmission or broader neuromodulatory influence, is a primary player in the Alzheimer’s disease process. The changes in neural activation and memory performance in response to an acute cholinergic challenge demonstrate the malleability of these systems and potential for treatment influence. The underlying state of the cholinergic system is a factor in the extent and perhaps the direction of this response. The work also highlights the value of research approaches that include multiple measures to simultaneously address the state of brain structures, focal proteinopathies, cortical function, neurotransmitter influence, and clinical symptoms. Clinical neuroscience research commonly measures an association between an individual brain structure or function and a clinical state, providing a limited view of causal mechanisms (Etkin et al., 2018). Measuring several structural, physiological, and functional brain features in the study group, particularly in longitudinal designs, can help reveal key causal factors, inter-relationships, and links to clinical symptoms. This can lead to a more comprehensive and holistic understanding of how Alzheimer’s disease unfolds. In addition, studies that address clinical heterogeneity in the sample, such as sex, race, age, specific cognitive deficits, and neuropsychiatric symptoms, will be useful. Finally, as demonstrated by the Richter et al. study, research that employs an intervention that serves as a bioprobe to manipulate a specific biological factor can help define critical mechanisms and identify potential targets for prevention or treatment of Alzheimer’s disease symptoms. The cholinergic system returns to the stage. Glossary 11C-N-methyl-4-piperidyl acetate PET imaging (MP4A): A PET imaging technique to measure regional acetylcholinesterase enzyme activity in the cortex, based on uptake of the injected ligand as a substrate for the enzyme. The images are voxel maps of this activity and are considered to represent the number or functional activity of local cholinergic neurons, or the effect of a cholinesterase inhibitor drug. Acetylcholinesterase: An enzyme involved in acetylcholine degradation. Brain cholinergic system: Brain structures and functions associated with acetylcholine as the neurotransmitter. The system includes: Basal forebrain: A locus for many acetylcholine-containing neurons. It contains subregions such as the nucleus basalis of Meynert (Ch4) that each have topographic projections to specific cortical regions. Cholinergic neurons: Neuronal tracts that typically extend from structures such as basal forebrain to the cortex. Cholinergic receptors: Neuroreceptors that respond to acetylcholine. There are nicotinic and muscarinic subtypes and both are widely distributed in the cortex. They have direct postsynaptic neurotransmitter effects as well as broader neuromodulatory effects. References Etkin A. Addressing the causality gap in human psychiatric neuroscience. JAMA Psychiatry 2018; 75: 3– 4. Google Scholar CrossRef Search ADS PubMed Grothe MJ, Ewers M, Krause B, Heinsen H, Teipel SJ. Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement 2014; 10: 344– 53. Google Scholar CrossRef Search ADS Mesulam MM. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. J Comp Neurol 2013; 521: 4124– 44. Google Scholar CrossRef Search ADS PubMed Ovsepian SV, O'Leary VB, Zaborszky L. Cholinergic mechanisms in the cerebral cortex: beyond synaptic transmission. Neuroscientist 2016; 22: 238– 51. Google Scholar CrossRef Search ADS PubMed Richter N, Beckers N, Onur OA, Dietlein M, Tittgemeyer M, Kracht L, et al. Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease. Brain 2018, in press. doi: 10.1093/brain/awx356. Schmitz TW, Nathan Spreng R. Alzheimer's Disease Neuroimaging Initiative. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology. Nat Commun 2016; 7: 13249. Google Scholar CrossRef Search ADS PubMed Sultzer DL, Melrose RJ, Riskin-Jones H, Narvaez TA, Veliz J, Ando TK, et al. Cholinergic receptor binding in vivo and cognitive skills in healthy aging, MCI, and Alzheimer's disease. Alzheimers Dement 2017; 13: P779– 80. Google Scholar CrossRef Search ADS Wolf D, Grothe M, Fischer FU, Heinsen H, Kilimann I, Teipel S, et al. Association of basal forebrain volumes and cognition in normal aging. Neuropsychologia 2014; 53: 54– 63. Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Guarantors of Brain 2018. This work is written by a Government employee and is in the public domain in the US.
Brain – Oxford University Press
Published: Mar 1, 2018
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