**Additional materials**

Several previous studies on 153 MCI and AD patients involved in the short- (4 months) and medium-term (12 months) administration of intranasal insulin using the ViaNase device to deliver the drug confirm the findings of the preservation of*caregiver-rated functional ability* in MCI and AD patients. The first randomized, placebo-controlled pilot study of ViaNase delivered intranasal insulin consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40), all of whom were treated with 20 and 40 IU daily dosages of intranasal insulin for 4 months (9). The mean patient age was 71 years old, and the mean 3MSE score was 83.7–84.3 [20 IU/40 IU]. 50–57% were positive for the high-risk apolipoprotein E epsilon-4 allele. The following results were reported: "Treatment with 20 IU of insulin *improved delayed memory* **(***P* < .05), and both doses of insulin (20 and 40 IU) *preserved caregiver-rated functional ability* **(***P* **<** .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD **(***P* **<** .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression." The second placebo-controlled study of ViaNase delivered intranasal insulin administration consisted of 49 of 289 patients with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD) who were randomized to receive either insulin or placebo daily for 12 months [70].9 This was a phase 2/3 trial at 26 US sites and a change in cognitive function from baseline to 12 months served as the primary endpoint, with the primary outcome measuring the Alzheimer's

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competence of a person with AD.

*Intranasal Insulin as Promising Therapy for Preserving Pragmatic Competence in MCI and AD*

Disease Assessment Scale-Cognition measure (ADAS-Cog 12). The ViaNase delivered intranasal insulin *slowed the annual progress of cognitive decline by 50%*—or only a 2.5 point decline per patient on the ADAS-Cog12 versus the 5-point decline per patient of the placebo group. This significant "separation was evident at 3 months and continued

The finding in this chapter of the reduction of caregiver stress after the longer-

term administration (3 plus years) of intranasal insulin is also evident from qualitative findings from an open-label study of 22 MCI and AD patients on the compassionate use of intranasal insulin.10 These patients displayed, before ViaNase delivered treatment, significant symptoms of social and linguistic withdrawal, flattening of affect, and irritability, as well as moderate to high levels of familyreported caregiver stress [1–3, 60]. Several publications also extensively document treatment-mediated improvements in language, visuospatial, and, in particular, executive functioning test scores of patients at moderate AD and an early MCI patient (5) and a return of pragmatic competence in the areas of jokes, self-expression, and empathy in early and moderate AD and MCI patients [1, 60]. Over 90% of caregivers of the 22 compassionate use patients also reported moderate to very strong reductions in caregiver stress after 1 year of intranasal insulin administration

<sup>10</sup> These MCI and AD patients live in naturalistic settings (2011–present) and provide linguistic evidence on phenomena as they naturally occur, i.e., they provide conversational data for the case study methodology as used by sociologists for the purpose of theory development and building. Hamilton [72] found that it is only in such conversations that it is possible to describe the full range of communicative

*DOI: http://dx.doi.org/10.5772/intechopen.90725*

to their family members [1, 60, 73, 74].

to widen over the course of the [12 month] study" [71].

<sup>8</sup> In the olfactory system, the sites that are affected include the anterior olfactory nucleus, the uncus, and the medial group of amygdaloid nuclei—all receives fibers directly from the olfactory bulb ([69]:4534).

<sup>9</sup> Assessments were made at baseline and at 3-month intervals until the end of the study, when participants were offered open-label insulin treatment for another 6 months. The other 240 patients used a different device (Precisions Olfactory Delivery [POD]) which failed to produce any difference in outcome on the ADAS-Cog 12 measure at 12 months with the placebo group. Both POD and placebo groups increased by about 4 points on the ADAS-Cog 12 measure, indicating worsening. Nor were there any changes in any other Alzheimer-related biomarkers like amyloid-beta 40 and 42, total tau, or phosphorylated tau (Clinical Neurology News 12/4/18:2). The model is controlled for age, sex, genetic risk status, and investigation site. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. Around 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.

### *Intranasal Insulin as Promising Therapy for Preserving Pragmatic Competence in MCI and AD DOI: http://dx.doi.org/10.5772/intechopen.90725*

Disease Assessment Scale-Cognition measure (ADAS-Cog 12). The ViaNase delivered intranasal insulin *slowed the annual progress of cognitive decline by 50%*—or only a 2.5 point decline per patient on the ADAS-Cog12 versus the 5-point decline per patient of the placebo group. This significant "separation was evident at 3 months and continued to widen over the course of the [12 month] study" [71].

The finding in this chapter of the reduction of caregiver stress after the longerterm administration (3 plus years) of intranasal insulin is also evident from qualitative findings from an open-label study of 22 MCI and AD patients on the compassionate use of intranasal insulin.10 These patients displayed, before ViaNase delivered treatment, significant symptoms of social and linguistic withdrawal, flattening of affect, and irritability, as well as moderate to high levels of familyreported caregiver stress [1–3, 60]. Several publications also extensively document treatment-mediated improvements in language, visuospatial, and, in particular, executive functioning test scores of patients at moderate AD and an early MCI patient (5) and a return of pragmatic competence in the areas of jokes, self-expression, and empathy in early and moderate AD and MCI patients [1, 60]. Over 90% of caregivers of the 22 compassionate use patients also reported moderate to very strong reductions in caregiver stress after 1 year of intranasal insulin administration to their family members [1, 60, 73, 74].

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

olfactory pathway (hypothesized to be affected early on in AD).8

achievement that deserves further application and investigation.

to receive either insulin or placebo daily for 12 months [70].9

trial at 26 US sites and a change in cognitive function from baseline to 12 months served as the primary endpoint, with the primary outcome measuring the Alzheimer's

<sup>8</sup> In the olfactory system, the sites that are affected include the anterior olfactory nucleus, the uncus, and the medial group of amygdaloid nuclei—all receives fibers directly from the olfactory bulb ([69]:4534). <sup>9</sup> Assessments were made at baseline and at 3-month intervals until the end of the study, when participants were offered open-label insulin treatment for another 6 months. The other 240 patients used a different device (Precisions Olfactory Delivery [POD]) which failed to produce any difference in outcome on the ADAS-Cog 12 measure at 12 months with the placebo group. Both POD and placebo groups increased by about 4 points on the ADAS-Cog 12 measure, indicating worsening. Nor were there any changes in any other Alzheimer-related biomarkers like amyloid-beta 40 and 42, total tau, or phosphorylated tau (Clinical Neurology News 12/4/18:2). The model is controlled for age, sex, genetic risk status, and investigation site. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. Around 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.

Several previous studies on 153 MCI and AD patients involved in the short- (4 months) and medium-term (12 months) administration of intranasal insulin using the ViaNase device to deliver the drug confirm the findings of the preservation of*caregiver-rated functional ability* in MCI and AD patients. The first randomized, placebo-controlled pilot study of ViaNase delivered intranasal insulin consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40), all of whom were treated with 20 and 40 IU daily dosages of intranasal insulin for 4 months (9). The mean patient age was 71 years old, and the mean 3MSE score was 83.7–84.3 [20 IU/40 IU]. 50–57% were positive for the high-risk apolipoprotein E epsilon-4 allele. The following results were reported: "Treatment with 20 IU of insulin *improved delayed memory* **(***P* < .05), and both doses of insulin (20 and 40 IU) *preserved caregiver-rated functional ability* **(***P* **<** .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD **(***P* **<** .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression." The second placebo-controlled study of ViaNase delivered intranasal insulin administration consisted of 49 of 289 patients with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD) who were randomized

**Additional materials**

potentially arrest the further spread of the disease process in the involvement of the hippocampus, areas of the neocortex in the parietotemporal and frontal lobes, as well as hypothalamic inflammation linked to age and disease-related declines in insulin sensitivity [4, 46]. One patient after 8 months of intranasal insulin was administered a series of pre- and post-therapy neuropsychological tests, including visuospatial skills, visual spatial ability, visual working memory, and executive functioning after beginning intranasal insulin [2]. Eight months later, his neurologist concluded that: "There was about a two-year reversal of cognitive impairment while receiving intranasal insulin, going from mild dementia to mild cognitive impairment [3]." A return to MCI from early AD is a significant therapeutic

This could

This was a phase 2/3

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<sup>10</sup> These MCI and AD patients live in naturalistic settings (2011–present) and provide linguistic evidence on phenomena as they naturally occur, i.e., they provide conversational data for the case study methodology as used by sociologists for the purpose of theory development and building. Hamilton [72] found that it is only in such conversations that it is possible to describe the full range of communicative competence of a person with AD.

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*
