Early Intranasal Insulin Therapy Halts Progression of Neurodegeneration

Progress in Alzheimer's Disease Therapeutics

Suzanne M de la Monte

Disclosures

Aging Health. 2012;8(1):61-64. 

In This Article

Discussion

AD is the most common cause of dementia in the western hemisphere, and equally alarming is the fact that AD is now emerging as a public health problem in developing countries as well. Although aging is the most important correlate of AD, other factors are clearly involved, since most elderly individuals do not succumb to AD. For nearly 30 years, researchers focused mainly on the role of genetics as causal agents, despite evidence that the majority of AD cases occur sporadically. Only within the past few years have investigators come to realize that AD rates increased sharply over the past 40–50 years, even after adjusting for aging within the population.[2] Certainly, such a time course is too brief to account for the shift in trends. What finally caused a sea of change in our thinking were the pivotal discoveries that AD is associated with brain insulin resistance and insulin deficiency, mimicking the effects of diabetes mellitus, and the rates of MCI and dementia are significantly higher among diabetics than nondiabetics.[3] The concept that AD may be a brain form of diabetes fits well with earlier evidence that deficits in brain energy metabolism, particularly glucose utilization, start early in the course of the disease and progress with its severity. Since deficiencies in brain metabolism are detectable by noninvasive imaging techniques, such as PET scans, these types of approaches could be used to help diagnose AD and monitor its progression.

The work by Craft et al. represents an important contribution to the field of AD therapeutics. In addition to forwarding research on a newer and probably less costly approach to treatment, the study builds on the emerging concept that AD is fundamentally mediated by progressive brain insulin deficiency and resistance.[4,5] Brain metabolic disturbances, particularly the ability to utilize glucose, its main fuel, arise very early and could possibly initiate disease.[6–8] Without insulin, brain cells, including neurons, oligodendrocytes (myelin-producing) and vascular elements function poorly and degenerate or die.[9] Therefore, early detection and correction of brain insulin deficiency and resistance are critical to our ability to halt AD progression and perhaps prevent its development. The underlying hypothesis embodied in this work is well supported by experimental evidence that impairments in brain insulin actions cause neurodegeneration with loss of neurons (brain atrophy), Aβ42 accumulation/toxicity, phospho-tau pathology and neuroinflammation, and decreased brain metabolism and Aβ42 clearance.[3] Early intervention to resupply the missing trophic factor (i.e., insulin) would support viability and function of the various cell types needed to sustain cognition, and would also likely prevent or slow the process of Aβ42 and phospho-tau-induced neurodegeneration.

The article by Craft et al. puts the whole story about the importance of insulin as a neuroprotective agent into excellent clinical perspective because the researchers utilized human subjects in a randomized, double-blind, placebo-controlled trial. Although the study was limited in duration, the results are very promising, particularly for the populations targeted in the study (i.e., MCI and early AD). The authors' conclusion that individuals in the early stages of AD and those with MCI (pre-AD) might benefit from intranasal insulin therapy is correct and supported by the results. The rationale for studying subjects with MCI is thoroughly justified because that group is at a significantly increased risk for developing AD, and the ultimate goal of any research in this field is disease prevention. Consideration for the use of insulin therapy in AD is supported by the earlier findings that:

  • Diabetic patients who were well managed with insulin had improved memory and reduced rates of AD progression;

  • Elderly diabetics who were treated with insulin had less severe AD brain pathology compared with nondiabetics;

  • Short trials of insulin treatment improved cognition and memory in subjects with AD;

  • Hyper-insulinemic euglycemic clamping (high insulin with normal glucose) enhances cognition and attention in AD;

  • In experimental animals, brain insulin treatments improved memory, cognition and neurotransmitter function.[3]

Although the abovementioned observations present an optimistic picture that seems to clear the path toward the use of insulin therapy in AD, from both clinical and public health perspectives, extreme caution must be exercised in utilizing this approach in the targeted geriatric population. Important concerns include inadvertent bouts of hypoglycemia that could lead to traumatic falls and life-threatening metabolic insults, thus limiting the potential use of insulin therapy. Systemic insulin therapy for treating AD in elderly populations requires careful consideration and extensive monitoring to minimize or avoid harm, and therefore is not entirely feasible for routine medical care in geriatric populations. On the other hand, the administration of insulin via the intranasal route holds promise for safety and efficacy, as most of the insulin delivered properly in this manner will go to the brain and not adversely affect peripheral blood glucose levels. In the study by Craft et al., in addition to demonstrating efficacy, they determined that intranasal insulin therapy was safe for elderly patients.

The main objectives of the study by Craft et al., were to examine the effects of intranasal insulin on cognitive function, cerebral glucose metabolism and CSF biomarkers related to MCI and AD. The subtext of their study design and conclusions is that while intranasal insulin monotherapy can benefit individuals in the early stages or pre-stages of AD, given our understanding about how AD progresses, it is unlikely that this approach will be as effective in patients who have reached later stages of neurodegeneration. Researchers studying AD realize that once AD becomes established and reaches a certain stage, it is difficult and perhaps impossible to slow its course or halt its progression. Insulin therapy may improve cognitive performance as long as neurons and other cell types in the brain retain their capacities to survive and function in response to insulin stimulation. As AD progresses into the later stages of disease, the brain becomes increasingly more insulin resistant, a similar problem to that found in Type 2 diabetes.[3,5] As AD progresses, intranasal insulin monotherapy may support fewer and fewer cells in the brain, necessitating the use of additional therapeutic targets and approaches.

Certainly, the demonstration that intranasal insulin monotherapy is safe and effective for treating individuals with MCI and early AD is exciting and holds promise, particularly since standard objective measures were used to document outcomes. Extensions of this trial to larger populations with well-defined clinical criteria for MCI or early AD diagnoses should be considered high priority in the near future. However, moving beyond the present and near future, consideration should be given to the next steps that would take into account our current limitations in efficiently detecting and diagnosing MCI and AD. Researchers throughout this field recognize that neurodegeneration is a progressive process that eventually seems to drive itself. Correspondingly, there is considerable evidence that Aβ42 toxicity impairs insulin signaling and promotes tau pathology, and that both tau and Aβ42 pathology promote oxidative stress, inflammation, metabolic embarrassment and cell loss, which worsen brain insulin resistance.[10] In other words, each component of neurodegeneration negatively impacts the others and thereby advances the pathology that mediates AD dementia. Since all components of the cascade eventually contribute to neurodegeneration, the later stages of AD will require multipronged therapeutic measures to be effective. Fortunately, there is already a wealth of information available about the treatment and management of Type 2 diabetes, which is fundamentally caused by insulin resistance in the body and is now recognized to be associated with cognitive impairment and to contribute to early dementia.

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