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AboEl-Azm et al. | Journal of Clinical and Translational Research 2023; 9(4): 222-235 223
amyloid peptide and tau protein phosphorylation [3]. Low insulin 2.2. Search strategy
levels in the central nervous system (CNS) may be caused by
impaired insulin transport through the blood-brain barrier (BBB). Three electronic databases (PubMed, Scopus, and Web of
Therefore, raising brain insulin may stop the degenerative Science) were searched from their inception until August 2022
processes associated with AD [3]. Based on that, a wide range using the following query: (Alzheimer OR [Senile Dementia] OR
of pharmacological substances and delivery strategies has been [Dementia Presenile]) AND [Insulin OR Novolin OR Iletin]).
developed and studied. 2.3. Selection process
The olfactory bulb, cerebral cortex, hippocampus,
hypothalamus, cerebellum, and choroid plexus have the highest The titles and abstracts of all citations considered for inclusion
insulin receptor density [4]. Accordingly, through the roof of the were reviewed by three authors independently. Then, we extracted
nose, insulin can cross through the BBB and systemic circulation, the full text of the selected studies to evaluate their applicability
entering the brain through the olfactory, trigeminal, and nerve and validated them according to our systematic review and meta-
fiber pathways [5]. analysis standards. Discrepancies were resolved by consensus.
Binding insulin with its receptor will lead to autophosphorylation 2.4. Data extraction
of the insulin receptor and induction of insulin receptor substrate
(IRS). Activation of AKT, which is one of the signaling routes that Data were extracted from an online data extraction sheet by
insulin activates, through IRS phosphorylation has been linked four independent authors. The extracted data included: (1) A
to improvements in neuronal protection, learning, and memory summary of the included studies, (2) baseline characteristics for
functions among AD patients [6]. the included population, (3) risk of bias domains, and (4) outcome
However, several previous studies have shown conflicting measures. Any disagreements were solved by a fifth author.
findings regarding the influence of intranasal insulin on dementia
in AD patients. Therefore, in this study, we aimed to fill the 2.5. Quality appraisal
gap in detecting the real effect of intranasal insulin on these We used the Cochrane assessment tool 2 (ROB2) for randomized
patients. controlled trials [8]. Using that tool, each study was assessed for

2. Materials and Methods the possibility of bias in the following domains: (1) Random
sequence generation, (2) allocation concealment, (3) blinding of
This systematic review and meta-analysis were reported participants, personnel, and outcome assessors, (4) incomplete
following the PRISMA declaration requirements [7]. The outcome data, (5) selective outcome data reporting, and (6) other
protocol of this study was registered on the PROSPERO sources of bias. The degree of bias in the authors’ conclusions is
(CRD42022355827). classified as “low risk,” “some concerns,” or “high risk.”

2.1. Eligibility criteria 2.6. Synthesis methods
The following conditions were considered for the study: Continuous were pooled as mean difference (MD) between
(i) Population: Studies on patients who have AD or mild the two groups from baseline to the endpoint in the meta-analysis
cognitive impairment. models utilizing the inverse variance (IV) method. We assumed
(ii) Intervention: Studies where the exposed group was intranasal a fixed-effect model of the MD as the main analysis model.
insulin. Nevertheless, relative risk (RR) was used to pool dichotomous
(iii) Comparator: Studies where the control group received a data in a fixed-effect model using the Mantel-Haenszel (M-H)
placebo. method. RevMan software (version 5.4 for Windows) was applied
(iv) Outcome: Studies stated one or more of the following to run the statistical analysis. In addition, we used the Chi-square
outcomes: Alzheimer Disease’s Assessment Scale- test (Cochrane Q test) to assess the statistical heterogeneity of
cognitive subscale (ADAS-cog) either 40 IU or 20 IU, the included studies. Significant heterogeneity was reflected by
and adverse effects (headache, fall, and rhinitis/upper I > 50% with P < 0.1.
2
respiratory infection [URI]). In addition, memory
composite (delayed story recall) 40 IU and 20 IU, dementia 3. Results
severity rating scale (DSRS), AD cooperative study- 3.1. Results of study selection and characteristics
activities of daily living (ADCS-ADL), clinical dimension
rating-sum of boxes (CDR-SOB), and cerebral spinal fluid Our literature search process retrieved 9119 records. After
(CSF) biomarkers of AD. removing duplicates, 6391 abstracts were evaluated, and 19
(v) Study design: Studies that were designated as randomized articles were eligible for full-text screening. Of them, 12 studies
clinical trials (RCTs). were included in this study. Due to the heterogeneity in some
(vi) Studies excluded: Not published in the English language, included studies, we conducted a meta-analysis of seven studies.
comments, review articles, case reports, observational The PRISMA flow diagram of the study selection process is
studies, abstracts, and letters to the editor. shown in Figure 1.

DOI: http://dx.doi.org/10.18053/jctres.09.202304.23-00013