You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial
Abstract 1:
Background : The 22q13 deletion syndrome ( Phelan – McDermid syndrome ) is characterised by a global developmental delay , absent or delayed speech , generalised hypotonia , autistic behaviour and characteristic phenotypic features . Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease . Aims : To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome . Methods : We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year . Short-term ( during the first 6 weeks ) and long-term effects ( after 12 months of treatment ) on motor skills , cognitive functions , or autonomous functions , speech and communication , emotional state , social behaviour , behavioural disorders , independence in daily living and education were assessed . Results : The children showed marked short-term improvements in gross and fine motor activities , cognitive functions and educational level . Positive long-term effects were found for fine and gross motor activities , nonverbal communication , cognitive functions and autonomy . Possible side effects were found in one patient who displayed changes in balance , extreme sensitivity to touch and general loss of interest . One patient complained of intermittent nose bleeding . Conclusions : We conclude that long-term administration of intranasal insulin may benefit motor development , cognitive functions and spontaneous activity in children with 22q13 deletion syndrome


Title 2:
Association of diabetes mellitus and dementia: The Rotterdam Study
Abstract 2:
Summary Dementia and non-insulin-dependent diabetes mellitus ( NIDDM ) are highly prevalent disorders in the elderly . Diabetes has repeatedly been reported to affect cognition , but its relation with dementia is uncertain . We therefore studied the association between diabetes and dementia in the Rotterdam Study , a large population -based study in the elderly . Of 6330 participants , aged 55 to 99 years old , complete information on diabetes and presence of dementia was available . Diabetes was diagnosed as use of anti-diabetes medication or r and om or post-load serum glucose over 11 mmol/l . Dementia was diagnosed through a stepped approach , including a sensitive screening of all participants and a comprehensive diagnostic work-up . Diabetes was present in 724 ( 11.4 % ) subjects . Of the 265 dementia patients 59 ( 22.3 % ) had diabetes . Multiple logistic regression analyses , adjusting for age and sex differences , revealed a positive association between diabetes and dementia ( odds ratio : 1.3 , 95 % confidence interval : 1.0–1.9 ) . In particular , strong associations were found between dementia and diabetes treated with insulin ( odds ratio : 3.2 , 95 % confidence interval : 1.4–7.5 ) . The relation was strongest with vascular dementia , but was also observed with Alzheimer 's disease . These associations were independent of educational attainment , smoking , body mass index , atherosclerosis , blood pressure and antihypertensive drug treatment , and could not be explained by clinical cerebral infa rct ions . The results suggest that NIDDM is associated with dementia . Alzheimer 's disease may be more frequent in elderly diabetic patients treated with insulin  . [ Diabetologia ( 1996 ) 39 : 1392–1397


Title 3:
Intranasal insulin improves memory in humans
Abstract 3:
Previous studies have suggested an acutely improving effect of insulin on memory function . To study changes in memory associated with a prolonged increase in brain insulin activity in humans , here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment . Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration , we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function . Also , improvements in mood were expected . We investigated the effects of 8 weeks of intranasal administration of insulin ( human regular insulin 4 x 40 IU/d ) on declarative memory ( immediate and delayed recall of word lists ) , attention ( Stroop test ) , and mood in 38 healthy subjects ( 24 males ) in a double blind , between-subject comparison . Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions . Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration ( words recalled , Placebo 2.92 + /- 1.00 , Insulin 6.20 + /- 1.03 , p < 0.05 ) . Moreover , subjects after insulin reported signs of enhanced mood , such as reduced anger ( p < 0.02 ) and enhanced self-confidence ( p < 0.03 ) . Results indicate a direct action of prolonged intranasal administration of insulin on brain functions , improving memory and mood in the absence of systemic side effects . These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer 's disease


Title 4:
Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype
Abstract 4:
Raising insulin acutely in the periphery and in brain improves verbal memory . Intranasal insulin administration , which raises insulin acutely in the CNS without raising plasma insulin levels , provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes . Based on prior research with intravenous insulin , we predicted that the treatment response would differ between subjects with ( epsilon4 + ) and without ( epsilon4- ) the APOE-epsilon4 allele . On separate mornings , 26 memory-impaired subjects ( 13 with early Alzheimer 's disease and 13 with amnestic mild cognitive impairment ) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline ( placebo ) or insulin ( 20 or 40 IU ) . Cognition was tested 15 min post-treatment , and blood was acquired at baseline and 45 min after treatment . Intranasal insulin treatment did not change plasma insulin or glucose levels .  Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults . These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4 + subjects and normal adults . Unexpectedly , memory-impaired epsilon4 + subjects showed poorer recall following insulin administration on one test of memory . These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E ( APOE ) related differences in insulin metabolism


Title 5:
Central nervous system effects of intranasally administered insulin during euglycemia in men.
Abstract 5:
Insulin receptors have been detected in several structures of the brain , yet the biological significance of insulin acting on the brain remains rather unclear . In humans , direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels . Since several intranasally administered viruses , peptides , and hormones have been shown to penetrate directly from the nose to the brain , we tested whether insulin after intranasal administration likewise has access to the brain . After a 60-min baseline period , insulin ( 20 IU H-Insulin 100 Hoechst ) or vehicle ( 2.7 mg/ml m-Cresol ) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design . Auditory-evoked potentials ( AEP ) indexing cortical sensory processing were recorded while the subjects performed a vigilance task ( oddball paradigm ) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo .  Blood glucose and serum insulin levels were not affected by intranasal insulin . Compared with placebo , intranasal administration of insulin reduced amplitudes of the N1 ( P < 0.005 ) and P3 ( P < 0.02 ) components of the AEP and increased P3 latency ( P < 0.05 ) . The reduction in P3 amplitude was most pronounced over the frontal recording site ( 2.42 + /- 1.00 vs. 4.92 + /- 0.79 microV , P < 0.0005 ) . At this site , after insulin administration , a broad negative shift developed in the AEP between 280 and 500 ms poststimulus ( area under the curve -166.0 + /- 183.8 vs. 270.8 + /- 138.7 microV x ms after placebo , P < 0.01 ) . The results suggest that after intranasal administration , insulin directly enters the brain and exerts distinct influences on central nervous functions in humans


Title 6:
Dissociable contributions within the medial temporal lobe to encoding of object-location associations.
Abstract 6:
The crucial role of the medial temporal lobe ( MTL ) in episodic memory is well established . Although there is little doubt that its anatomical subregions-the hippocampus , peri- , entorhinal and parahippocampal cortex (PHC)-contribute differentially to mnemonic processes , their specific functions in episodic memory are under debate . Data from animal , human lesion , and neuroimaging studies suggest somewhat contradictory perspectives on this functional specialization : a general participation in declarative memory , an exclusive involvement in associative mnemonic processes , and a specific contribution to spatial memory are reported for the hippocampus , adjacent cortices , and the PHC . A functional lateralization in humans dependent on the verbalizability of the material is also discussed herein . To further eluci date the differential contributions of the various MTL subregions to encoding , we employed an object-location association memory paradigm . The memory for each of the studied associations was tested twice : by the object , and by the location serving as retrieval cue . The memory accuracy in response to both cue types was also assessed parametrically . Brain activity during encoding which leads to different degrees of subsequent memory accuracy under the two retrieval conditions was compared . We found the bilateral posterior PHC to participate in encoding of both the object associated with a location and the location associated with an object . In contrast , activity in an area in the left anterior PHC and the right anterior MTL was only correlated with the memory for the location associated with an object
The current limited clinical experience suggests potential beneficial cognitive effects of intranasal insulin .
Analyses provide clinical considerations for future research aim ed at elucidating whether intranasal insulin may be used to improve cognitive functions