**4.3 5 ½ years after AD diagnosis and 5 years on insulin therapy: less atrophy of occipital and thalamic structures**

At year 5 ½ after AD diagnosis and at 5 years receiving intranasal insulin therapy (12/17–12/18), AR was still able to inferentially reason. He was also fully ambulatory, eating with the mild AD patients at his nursing home, and looked at books and TV while paying attention to both. His visual skills were also still intact. For example, one day AR was walking independently back to his room with his daughter and headed toward a large automatic opening and closing door to the Alzheimer wing which was being held open by a staff member. AR immediately turned to his daughter and asked: "Can we go through?" His daughter responded: "Yes." Then AR was able to remember, proceeded to analyze contextual information and to simultaneously warn her of possible impending danger, telling her: "Hurry up. It closes fast" [3].

**Figure 4** is AR's CT scan at 5 years receiving intranasal insulin therapy (5 ½ years after AD diagnosis) (4/18). **Figure 5a** and **b** presents subcortical segmentation of MRI scans after boundary correction of a subject classified as MCI (4a) and of a subject diagnosed with probable Alzheimer's disease (4b) [26].

Consistent with our hypothesis that extended therapeutic usage should slow AD disease progression, AR's 4/18 CT scans demonstrate that his occipital lobe does not show a significant shrinkage of gray matter volume (indicated by black arrow, **Figure 4**). Similarly, AR's thalamus, indicated by the yellow arrow (**Figure 4**), is also not as atrophied in terms of volume loss as the AD patient (**Figure 5b**) despite his significant frontal volume loss and lateral ventricle enlargement consistent with late-stage AD [50].

AR's retained volume in the occipital and thalamic subcortical structures supports previous findings that intranasal insulin directly reaches the occipital cortical brain regions and the thalamus in older adults [10]. These results suggest such enhanced insulin action in these brain areas can, in fact, slow AD disease progression.

**147**

**Figure 6.**

*(a) and (b): CT scans of patient AR, 4/18.*

**Figure 5.**

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

**Figure 6a** and **b** demonstrates how AR clearly shows signs of advanced AD by

*(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI* 

*(a) and of a subject diagnosed with probable Alzheimer's disease (b) (sagittal view) [26].*

*"Lateral ventricles are enlarged with disproportionate enlargement of the frontal horns. Temporal horns are both markedly enlarged, more so on the right. Third ventricle is moderately enlarged. Basel cisterns are enlarged, as are the sylvian fissures. Overall, findings are compatible with generalized volume loss, with disproportional frontal and temporal lobe volume loss. This includes medial temporal lobe volume loss with likely considerable hippocampal volume loss especially on the* 

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

4/18. AR's neurologist noted of his 4/18 CT scan:

*right. Sulci are not symmetrical on both sides [47]."*

**Figure 4.** *CT scan of patient AR, 4/18.*

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

### **Figure 5.**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

**occipital and thalamic structures**

to demonstrate capabilities in visual processing skills (occipital and parietal lobe functioning) as well as improvements in executive functioning under targeted therapy. At 3 years, he had returned to being able to ski (2019) after having lost the ability to manage his finances, shop, or independently go to doctor's visits [2].

**4.3 5 ½ years after AD diagnosis and 5 years on insulin therapy: less atrophy of** 

her of possible impending danger, telling her: "Hurry up. It closes fast" [3]. **Figure 4** is AR's CT scan at 5 years receiving intranasal insulin therapy (5 ½ years after AD diagnosis) (4/18). **Figure 5a** and **b** presents subcortical segmentation of MRI scans after boundary correction of a subject classified as MCI (4a) and

of a subject diagnosed with probable Alzheimer's disease (4b) [26].

At year 5 ½ after AD diagnosis and at 5 years receiving intranasal insulin therapy (12/17–12/18), AR was still able to inferentially reason. He was also fully ambulatory, eating with the mild AD patients at his nursing home, and looked at books and TV while paying attention to both. His visual skills were also still intact. For example, one day AR was walking independently back to his room with his daughter and headed toward a large automatic opening and closing door to the Alzheimer wing which was being held open by a staff member. AR immediately turned to his daughter and asked: "Can we go through?" His daughter responded: "Yes." Then AR was able to remember, proceeded to analyze contextual information and to simultaneously warn

Consistent with our hypothesis that extended therapeutic usage should slow AD disease progression, AR's 4/18 CT scans demonstrate that his occipital lobe does not show a significant shrinkage of gray matter volume (indicated by black arrow, **Figure 4**). Similarly, AR's thalamus, indicated by the yellow arrow (**Figure 4**), is also not as atrophied in terms of volume loss as the AD patient (**Figure 5b**) despite his significant frontal volume loss and lateral ventricle enlargement consistent with

AR's retained volume in the occipital and thalamic subcortical structures supports previous findings that intranasal insulin directly reaches the occipital cortical brain regions and the thalamus in older adults [10]. These results suggest such enhanced insulin action in these brain areas can, in fact, slow AD disease progression.

**146**

**Figure 4.**

*CT scan of patient AR, 4/18.*

late-stage AD [50].

*(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI (a) and of a subject diagnosed with probable Alzheimer's disease (b) (sagittal view) [26].*

**Figure 6a** and **b** demonstrates how AR clearly shows signs of advanced AD by 4/18. AR's neurologist noted of his 4/18 CT scan:

*"Lateral ventricles are enlarged with disproportionate enlargement of the frontal horns. Temporal horns are both markedly enlarged, more so on the right. Third ventricle is moderately enlarged. Basel cisterns are enlarged, as are the sylvian fissures. Overall, findings are compatible with generalized volume loss, with disproportional frontal and temporal lobe volume loss. This includes medial temporal lobe volume loss with likely considerable hippocampal volume loss especially on the right. Sulci are not symmetrical on both sides [47]."*

**Figure 6.** *(a) and (b): CT scans of patient AR, 4/18.*

**Figure 7.**

*(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI (a) and of a subject diagnosed with probable Alzheimer's disease (b) (axial view) [26].*

Yet, as (again) compared with probable AD (**Figure 7b**), AR demonstrates less overall volume loss even with respect to the medial temporal lobe. Furthermore, in AR's case, left hippocampus atrophy is less pronounced than right (**Figure 6a** and **b**). This is also a significant finding because, as de Jong et al. [26] found in their Alzheimer's disease group, volume reduction of the *left* hippocampus, putamen, and thalamus formed the strongest predictors for declining cognitive performance in Alzheimer's disease progression.

### **5. Discussion**

The potential of intranasal insulin to curb the development and progression of AD [57] is by avoiding decreases in cerebral glucose metabolic rate within a complex neuronal network which comprises the hypothalamus, hippocampus, thalamus, and cortical brain structures. A series of CT scan results of a patient receiving extended administered intranasal insulin usage shows delayed atrophy of key areas of the brain associated with cognitive, visual, executive, and pragmatic functioning as compared to disease progression in MCI to AD patients not receiving therapy. These findings, particularly those that demonstrate slowed atrophy of the thalamus and occipital lobe, strongly suggest that extended intranasal insulin treatment might slow disease progression by reducing some areas of neuronal atrophy in the (thalamus) cortico-pulvinar projection system [18] associated with the anomia typical of late-stage AD [58, 59]. They also highlight the importance of thalamic stimulation on language and cognition and the ability of the preservation of nuclei within the thalamus to regulate the transmission of information to the cortex and between cortical areas [21]. The reduced atrophy of the occipital lobes in this patient on extended intranasal insulin therapy is also significant because lesion studies have shown that the pulvinar is critically involved in visual perception, attention, and visually guided behavior [21], which can include directing visual attention to a cued location.

The slowing of atrophy of the thalamus is also consistent with the hypothesized medial pathway of insulin [2, 3, 60] in which the thalamus is reached via the olfactory tubercle. Future research is required to refine precisely how intranasal insulin promotes glucose utilization in these neuronal networks, i.e., through changes in hippocampal synaptic plasticity and/or by increasing synapse density and dendritic plasticity in structures that process visual input ([61]:216).

Future follow-up studies are needed to explore how intranasal insulin's potential effectivity for reducing transition rates from amnestic MCI to AD is related to preserving those neurological structures associated with pragmatic tasking.

**149**

the literature [57].7

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

Specifically, additional studies are required consisting of mapping out the bulk flow of intranasal insulin along the olfactory and trigeminal pathways between the nasal passages and the CNS into deeper structures within the medial temporal lobe (MTL) ([45, 62]:491). The region of the MTL showing the greatest atrophy in mild cognitive impairment is the entorhinal cortex, which is precisely part of the parahippocampal gyrus and is the same region that has been postulated by Braak and

Additional practical studies are necessary to understand the relationship between the olfactory system and the delivery route of intranasal insulin on such hippocampal structures within the MTL to further elucidate the potential of intranasal insulin therapy. AR's continuing pragmatic abilities including sarcastic utterances, utilizing empathic tone and pragmatic discourse markers [3] 6 years after AD diagnosis and 5 ½ years on intranasal insulin, point toward the partial effect of intranasal insulin on deeper hippocampal brain structures. The right parahippocampal gyrus, for example, has functions beyond the contextualizing of visual background stimuli and identifying social context such as the inclusion of paralinguistic elements of verbal communication resulting in the ability to employ sarcasm [63]. As Smith [43] notes: Many years (up to 50) before the symptoms (of AD) occur, neurofibrillary tangles start to form in neurons in the parahippocampal gyrus. At some stage, this process is exacerbated, and many projection neurons in the MTL then start to die, leading to atrophy of the lobe and to early signs of memory deficits. Once denuded of their input from the MTL, neurons in the target areas of neocortex show reduced activity, leading to slower metabolism and a fall in local blood flow. They will no longer function properly in the neural networks underlying higher cognition [64]. The findings in this chapter also illustrate, on a brain circuitry level, AR's other continued pragmatic capacities even with late-stage AD [2, 3]. Several weeks before his death from a post-hip surgery-related heart attack, AR was still able to employ a bodily related metaphor: "I am tired. It seems like that is all I say. What a pain in the ass that is." This statement involves the capacity to abstract and inhibit literal interpretation, both of which are associated with executive functioning tasks. Other linguistic evidence of AR's preserved pragmatic competence even 5.5 years after his AD diagnosis include telling jokes and using humor to assert autonomy [1–3]. The capacity to detect, understand, and respond to humor deteriorates significantly in the progression of AD [65]. Scholarship on the neural basis of humor processing precisely suggests that humor engages a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity [66]. The temporo-parietal junction incorporates information

Treatment-induced improvements in neuronal activity in the thalamus and occipital and parietal lobes can bring moderate to significant improvements in communication exchanges with caregivers, thereby reducing the AD patient's social and communicative isolation, lessen caregiver stress, and improve executive functioning. Furthermore, AR's annual, standard blood tests did not reveal abnormalities or indicators of chronic intranasal insulin therapy leading to

(further) desensitization of his brain insulin signaling [67] a concern expressed in

<sup>7</sup> Future studies can measure this potential through recent exosome biomarker tests derived from blood,

The results contained in this paper are the first published CT scans of a patient receiving extended intranasal insulin use. Begun at early MCI diagnosis, the extended use of intranasal insulin could substantially impact sites along the

plasma, and serum for the detection of brain insulin signaling resistance [68, 69].

Braak [40] to be the site where AD pathology is first expressed.

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

from the thalamus, among other systems.

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

Specifically, additional studies are required consisting of mapping out the bulk flow of intranasal insulin along the olfactory and trigeminal pathways between the nasal passages and the CNS into deeper structures within the medial temporal lobe (MTL) ([45, 62]:491). The region of the MTL showing the greatest atrophy in mild cognitive impairment is the entorhinal cortex, which is precisely part of the parahippocampal gyrus and is the same region that has been postulated by Braak and Braak [40] to be the site where AD pathology is first expressed.

Additional practical studies are necessary to understand the relationship between the olfactory system and the delivery route of intranasal insulin on such hippocampal structures within the MTL to further elucidate the potential of intranasal insulin therapy. AR's continuing pragmatic abilities including sarcastic utterances, utilizing empathic tone and pragmatic discourse markers [3] 6 years after AD diagnosis and 5 ½ years on intranasal insulin, point toward the partial effect of intranasal insulin on deeper hippocampal brain structures. The right parahippocampal gyrus, for example, has functions beyond the contextualizing of visual background stimuli and identifying social context such as the inclusion of paralinguistic elements of verbal communication resulting in the ability to employ sarcasm [63]. As Smith [43] notes:

Many years (up to 50) before the symptoms (of AD) occur, neurofibrillary tangles start to form in neurons in the parahippocampal gyrus. At some stage, this process is exacerbated, and many projection neurons in the MTL then start to die, leading to atrophy of the lobe and to early signs of memory deficits. Once denuded of their input from the MTL, neurons in the target areas of neocortex show reduced activity, leading to slower metabolism and a fall in local blood flow. They will no longer function properly in the neural networks underlying higher cognition [64].

The findings in this chapter also illustrate, on a brain circuitry level, AR's other continued pragmatic capacities even with late-stage AD [2, 3]. Several weeks before his death from a post-hip surgery-related heart attack, AR was still able to employ a bodily related metaphor: "I am tired. It seems like that is all I say. What a pain in the ass that is." This statement involves the capacity to abstract and inhibit literal interpretation, both of which are associated with executive functioning tasks. Other linguistic evidence of AR's preserved pragmatic competence even 5.5 years after his AD diagnosis include telling jokes and using humor to assert autonomy [1–3]. The capacity to detect, understand, and respond to humor deteriorates significantly in the progression of AD [65]. Scholarship on the neural basis of humor processing precisely suggests that humor engages a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity [66]. The temporo-parietal junction incorporates information from the thalamus, among other systems.

Treatment-induced improvements in neuronal activity in the thalamus and occipital and parietal lobes can bring moderate to significant improvements in communication exchanges with caregivers, thereby reducing the AD patient's social and communicative isolation, lessen caregiver stress, and improve executive functioning. Furthermore, AR's annual, standard blood tests did not reveal abnormalities or indicators of chronic intranasal insulin therapy leading to (further) desensitization of his brain insulin signaling [67] a concern expressed in the literature [57].7

The results contained in this paper are the first published CT scans of a patient receiving extended intranasal insulin use. Begun at early MCI diagnosis, the extended use of intranasal insulin could substantially impact sites along the

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

*(a) and of a subject diagnosed with probable Alzheimer's disease (b) (axial view) [26].*

Yet, as (again) compared with probable AD (**Figure 7b**), AR demonstrates less overall volume loss even with respect to the medial temporal lobe. Furthermore, in AR's case, left hippocampus atrophy is less pronounced than right (**Figure 6a** and **b**). This is also a significant finding because, as de Jong et al. [26] found in their Alzheimer's disease group, volume reduction of the *left* hippocampus, putamen, and thalamus formed the strongest predictors for declining cognitive performance in Alzheimer's

*(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI* 

The potential of intranasal insulin to curb the development and progression of AD [57] is by avoiding decreases in cerebral glucose metabolic rate within a complex neuronal network which comprises the hypothalamus, hippocampus, thalamus, and cortical brain structures. A series of CT scan results of a patient receiving extended administered intranasal insulin usage shows delayed atrophy of key areas of the brain associated with cognitive, visual, executive, and pragmatic functioning as compared to disease progression in MCI to AD patients not receiving therapy. These findings, particularly those that demonstrate slowed atrophy of the thalamus and occipital lobe, strongly suggest that extended intranasal insulin treatment might slow disease progression by reducing some areas of neuronal atrophy in the (thalamus) cortico-pulvinar projection system [18] associated with the anomia typical of late-stage AD [58, 59]. They also highlight the importance of thalamic stimulation on language and cognition and the ability of the preservation of nuclei within the thalamus to regulate the transmission of information to the cortex and between cortical areas [21]. The reduced atrophy of the occipital lobes in this patient on extended intranasal insulin therapy is also significant because lesion studies have shown that the pulvinar is critically involved in visual perception, attention, and visually guided

behavior [21], which can include directing visual attention to a cued location.

plasticity in structures that process visual input ([61]:216).

The slowing of atrophy of the thalamus is also consistent with the hypothesized medial pathway of insulin [2, 3, 60] in which the thalamus is reached via the olfactory tubercle. Future research is required to refine precisely how intranasal insulin promotes glucose utilization in these neuronal networks, i.e., through changes in hippocampal synaptic plasticity and/or by increasing synapse density and dendritic

Future follow-up studies are needed to explore how intranasal insulin's potential effectivity for reducing transition rates from amnestic MCI to AD is related to preserving those neurological structures associated with pragmatic tasking.

**148**

disease progression.

**5. Discussion**

**Figure 7.**

<sup>7</sup> Future studies can measure this potential through recent exosome biomarker tests derived from blood, plasma, and serum for the detection of brain insulin signaling resistance [68, 69].

olfactory pathway (hypothesized to be affected early on in AD).8 This could 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 achievement that deserves further application and investigation.
