Intranasal Insulin Shows Benefit in Mild Cognitive Impairment and Alzheimer's Disease

Susan Jeffrey

July 16, 2010

July 16, 2010 (Honolulu, Hawaii) — A small, randomized trial of 2 doses of intranasal insulin showed improvements in memory and functioning and improved CSF biomarker profiles among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) with treatment over placebo.

Four months of insulin delivered intranasally was associated with preservation, or in some cases, improvement on measures of cognitive function and functional status. There were also attendant improvements in cerebrospinal fluid (CSF) biomarker profiles and fludeoxyglucose (FDG) positron emission tomography (PET) imaging, showing preservation of activity in brain regions known to be critical in Alzheimer's pathology.

Dr. Suzanne Craft

"We believe our results are very promising, and they warrant future trials to determine the effects of longer-term administration on safety and other measures of efficacy, as well as on CSF biomarkers and PET imaging," lead author Suzanne Craft, PhD, from the University of Washington and VA Puget Sound, in Seattle, concluded.

Results of their randomized trial, dubbed the Study of Nasal Insulin to Fight Forgetfulness (SNIFF-120), were presented here at the Alzheimer's Association International Conference on Alzheimer's Disease 2010.

Sweet Smell of Preliminary Success

It is known that insulin plays a number of important roles in the brain, Dr. Craft said. Insulin receptors are distributed throughout the brain in regions related to memory and other cognitive activities, and insulin has a number of functions in the brain including maintenance of synapses and, importantly for AD pathology, amyloid-β (Aβ) regulation.

It has been shown that AD is associated with reduced insulin signaling and low CSF levels. Dr. Craft's group has shown reduced insulin levels in CSF that decreased further with increasing disease severity, and others have shown that the decrease in insulin occurs very early in the disease course.

Restoring normal insulin function to the brain then may have beneficial effects. "We thought that one of the most effective ways of doing this might be to administer insulin intranasally," Dr. Craft said. Given intranasally, insulin follows extracellular pathways to the brain, bypassing the periphery and the blood–brain barrier, the authors note.

This method, Dr. Craft said, "has been shown to increase CSF insulin very quickly and improve memory within a very short period of time, both in younger healthy adults, and...acutely in older adults with MCI and AD." Animal models confirm intranasal insulin makes a rapid appearance in areas important to memory, including the hippocampus, she added.

The SNIFF-120 trial was a 4-month, randomized, double-blind trial of placebo vs 2 doses of intranasal insulin: 20 or 40 IU daily. One hundred four patients with AD or amnestic MCI participated; patients with diabetes were excluded.

The insulin used in this study was standard commercially available insulin (Novo-Nordisk), delivered using a nebulizer designed to maximize delivery of the insulin into the upper nasal cavity, where it is transported into the brain.

All patients underwent cognitive testing at baseline and then at 2 and 4 months, and a subset had a lumbar puncture (n = 26) or resting FDG PET scanning (n = 40) at baseline and at 4 months. Primary outcome measures were the change from baseline to 4 months on the Alzheimer's Disease Assessment Scale–Cognitive Subscale and Delayed Story Recall scores.

Secondary measures included the Dementia Severity Rating Scale and the Alzheimer's Disease Cooperative Study Activity of Daily Living Scale, as well as the CSF and FDG PET measures.

Attenuation of Decline

Results at 4 months on the Alzheimer's Disease Assessment Scale–Cognitive Subscale showed a decline in the placebo group, Dr. Craft said, whereas there was "quite an attenuation of decline for patients in either the 20 IU or 40 IU dose of insulin" (P < .05 for both comparisons vs placebo).

The same pattern was seen in the Alzheimer's Disease Cooperative Study Activity of Daily Living Scale, with worsening in the placebo group and significant attenuation of worsening in both insulin dose groups.

However, Delayed Story Recall scores showed a substantial benefit with regard to memory vs placebo for the 20 IU dose (P < .05) that was not seen with the higher dose. Results on the Dementia Severity Rating Scale, a caregiver rating of function, showed a slight decline in the placebo group and improvement for both groups treated with insulin.

CSF biomarkers showed no change during 4 months of treatment in overall levels of Aβ42, but there was an improvement in the Aβ40/42 ratio. "A higher Aβ40/42 ratio is a beneficial profile, and we saw an increase in this ratio in the insulin-treated group," Dr. Craft noted.

Finally, compared with placebo patients, those in the insulin groups showed preserved glucose metabolism on FDG PET scanning in areas affected by AD pathology, including the posterior cingulate.

The safety was "excellent," she noted, and compliance with treatment was good.

The researchers plan to do another similar, but shorter, study with another type of insulin that binds to albumin, found abundantly in the brain. This different type of insulin increases insulin levels, similar to the effect of regular insulin, but levels go up and stay up for a longer time, she explained.

"If we see benefit with that formulation of insulin, then we'll compare it with the regular insulin we just tested in a bigger, longer trial" vs placebo, Dr. Craft told Medscape Medical News. "It's very safe, so I think we're ready to go very soon into a phase 3 trial."

A Boon for Therapy

Ralph Nixon, MD, PhD, from the Langone Medical Center and New York University, New York City, who moderated a press conference here featuring this and other papers, pointed out that a number of techniques are being developed to identify patients at risk before they develop clinical symptoms, at which point potential treatments may have the best chance of working.

"One of those modalities that might be applied at that early stage if Dr. Craft's work is further extended and confirmed, would involve insulin signaling stimulation," Dr. Nixon said. "And this would not only be a boon for therapy but would also catalyze a new way of looking at the mechanisms underlying the pathogenesis of AD, so it would really have 2 values."

However, he warned against people trying to use insulin in this way before more testing is done, with which Dr. Craft quickly agreed.

"Let's go on record with that," she told reporters here. "At this point it's not recommended that people try this at home. That being said, we're very encouraged, and I think we have the tools we need to go to the next step very easily of confirming this, but it's not ready for clinical use at this time."

"Striking" Effect of Diet on Amyloid

In a separate paper presented here, Dr. Craft and colleagues studied the effect of a high-fat/high-glycemic diet vs a low-fat/low-glycemic diet in a randomized feeding study conducted over the course of 4 weeks in 29 patients with MCI and 20 healthy adults. Diets were the same in terms of calories.

Cognitive testing and CSF collection were done at baseline and after the diet intervention.

Fasting plasma insulin, low-density lipoprotein, and total cholesterol levels were all increased by the high-fat/high-glycemic diet, whereas these parameters decreased with the low-fat/low-glycemic diet, with greater effects seen among those with MCI.

The effect of the diets on amyloid in the CSF was "striking," Dr. Craft noted. The low-fat diet moved Aβ42 levels in a beneficial direction for both the normal and MCI groups, beneficial being a lowering of Aβ42 and an increase in Aβ42 for those with MCI.

The high-fat diet, conversely, increased Aβ42 levels in the normal group, a pathological change. "The high-fat diet did not change levels for the MCI group, perhaps because the intervention was too brief to further exacerbate their pathology," Dr. Craft said.

The changes in lipoprotein-free CSF Aβ42 and CSF nonesterified fatty acids also predicted performance on tests of memory and attention, the authors write.

"It was incredible how powerful that intervention was, and people didn't even change their weight, they just switched what they ate," Dr. Craft told Medscape Medical News. "So, clearly these environmental factors are critical."

The study was supported by the National Institute on Aging and the Department of Veterans Affairs. Dr. Craft has disclosed no relevant financial relationships.

Alzheimer's Association International Conference on Alzheimer's Disease 2010: Abstract 04-04-01, Abstract 04-06-06. Presented July 14, 2010.


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