***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: There is compelling evidence that intranasal administration of regular human insulin ( RH-I ) improves memory in humans . Owing to the reduced tendency of its molecules to form hexamers , the rapid-acting insulin analog insulin aspart ( ASP-I ) is more rapidly absorbed than RH-I after subcutaneous administration . Since after intranasal insulin administration , ASP-I may also be expected to access the brain , we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans . Acute ( 40 IU ) and long-term ( 4 × 40 IU/day over 8 weeks ) effects of intranasally administered ASP-I , RH-I , and placebo on declarative memory ( word lists ) were assessed in 36 healthy men in a between-subject design . Plasma insulin and glucose levels were not affected . After 8 weeks of treatment , however , word list recall was improved compared to placebo in both the ASP-I ( p<0.01 ) and the RH-I groups ( p<0.05 ) . ASP-I-treated subjects performed even better than those of the RH-I-treated group ( p<0.05 ) . Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer 's disease Background : Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer ’s disease dementia ( AD ) or amnestic mild cognitive impairment ( MCI ) . The investigation of longer-term administration is necessary to determine whether benefits persist , whether they are similar to benefits provided by regular insulin , and whether either form of insulin therapy affects AD biomarkers . Objective : The present study aim ed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition , daily functioning , and AD biomarkers for adults with MCI or AD . Methods : This r and omized , double-blind , placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD . Participants received placebo ( n = 12 ) , 40 IU of insulin detemir ( n = 12 ) , or 40 IU of regular insulin ( n = 12 ) daily for four months , administered with a nasal delivery device . A cognitive battery was administered at baseline and after two and four months of treatment . MRI was administered for all participants and lumbar puncture for a subset ( n = 20 ) at baseline and four months . The primary outcome was change from baseline to four months on a memory composite ( sum of Z scores for delayed list and story recall ) . Secondary outcomes included : global cognition ( Alzheimer ’s Disease Assessment Scale-Cognition ) , daily functioning ( Dementia Severity Rating Scale ) , MRI volume changes in AD-related regions of interest , and cerebrospinal fluid AD markers . Results : The regular insulin treated group had better memory after two and four months compared with placebo ( p < 0.03 ) . No significant effects were observed for the detemir-assigned group compared with the placebo group , or for daily functioning for either group . Regular insulin treatment was associated with preserved volume on MRI . Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio . Conclusion : Future research is warranted to examine the mechanistic basis of treatment differences , and to further assess the efficacy and safety of intranasal insulin Mild-to-moderate AD patients were r and omized to placebo or rosiglitazone ( RSG ) 2 , 4 or 8 mg . Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive ( ADAS-Cog ) and Clinician 's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population ( N=511 ) , and results were also stratified by apolipoprotein E ( APOE ) genotype ( n=323 ) . No statistically significant differences on primary end points were detected between placebo and any RSG dose . There was a significant interaction between APOE ɛ4 allele status and ADAS-Cog ( P=0.014 ) . Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE ɛ4-negative patients on 8 mg RSG ( P=0.024 ; not corrected for multiplicity ) . APOE ɛ4-positive patients did not show improvement and showed a decline at the lowest RSG dose ( P=0.012 ; not corrected for multiplicity ) . Exploratory analyses suggested that APOE ɛ4 non-carriers exhibited cognitive and functional improvement in response to RSG , whereas APOE ɛ4 allele carriers showed no improvement and some decline was noted . These preliminary findings require confirmation in appropriate clinical studies Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Physical activity may help preserve cognitive function and decrease dementia risk , but epidemiologic findings are inconsistent . The authors conducted a prospect i ve study to determine the association between physical activity and risk of  dementia , Alzheimer 's disease , and vascular dementia . The US study population comprised 3,375 men and women aged 65 years or older , free of dementia at baseline , who participated in the Cardiovascular Health Cognition Study in 1992 - 2000 .  Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated . Analyses were based on Cox proportional hazards models . There were 480 incident cases of dementia over an average of 5.4 years of follow-up . After multivariate adjustment , participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 ( 95 % confidence interval : 0.61 , 1.19 ) compared with those in the lowest quartile , and participants engaging in > or=4 activities had a relative risk of dementia of 0.51 ( 95 % confidence interval : 0.33 , 0.79 ) compared with those engaging in 0 - 1 activity . These associations were more marked in apolipoprotein E genotype ( APOE ) epsilon4 allele noncarriers but were absent in carriers . A similar pattern was observed for Alzheimer 's disease and vascular dementia . Mechanisms to explain the observed relations deserve further study OBJECTIVE To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus ( DM ) . RESEARCH DESIGN AND METHODS This was a proof-of-concept , r and omized , double-blind , placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects . Measurements included regional perfusion , vasodilatation to hypercapnia with 3-Tesla MRI , and neuropsychological evaluation . RESULTS Intranasal insulin administration was well tolerated and did not affect systemic glucose levels . No serious adverse events were reported . Across all subjects , intranasal insulin  improved visuospatial memory ( P ≤ 0.05 ) . In the DM group , an increase of perfusion after insulin  administration was greater in the insular cortex compared with the control group ( P = 0.0003 ) . Cognitive performance after insulin administration was related to regional vasoreactivity . Improvements of visuospatial memory after insulin administration in the DM group ( R2adjusted = 0.44 , P = 0.0098 ) and in the verbal fluency test in the control group ( R2adjusted = 0.64 , P = 0.0087 ) were correlated with vasodilatation in the middle cerebral artery territory . CONCLUSIONS Intranasal insulin administration appears safe , does not affect systemic glucose control , and may provide acute improvements of cognitive function in patients with type 2 DM , potentially through vasoreactivity mechanisms . Intranasal insulin-induced  changes in cognitive function may be related to vasodilatation in the anterior brain regions , such as insular cortex that regulates attention-related task performance . Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy In previous studies , adults with Alzheimer 's disease ( AD ) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml , whereas normal adults ' memory was unchanged . Degree of memory enhancement was also related to apolipoprotein E ( apoE ) genotype status for AD patients . Response differences between normal and AD groups could reflect dose-response differences for insulin . To examine this question , 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order , result ing in five plasma insulin levels ( 10 , 25 , 35 , 85 and 135 microU/ml ) , while plasma glucose levels of ~100 mg/dl were maintained . Cognitive performance and plasma APP levels were measured after 120 min of infusion . Relative to baseline , AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml , whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml . Normal adults ' memory was also improved at insulin levels of 85 microU/ml . Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels ( 85 microU/ml ) than for normal adults and epsilon 4 homozygotes , who showed decreased APP at the 35 microU/ml level . AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects . In general , few effects of insulin  were seen at the highest dose for any subject group . These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern , and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation BACKGROUND Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease ( AD ) . Furthermore , intracerebroventricular or IV insulin administration improve memory , alter evoked potentials , and modulate neurotransmitters , possibly by augmenting low brain levels . After intranasal administration , insulin-like peptides follow extracellular pathways to the brain within 15 minutes . OBJECTIVE We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome , amnestic mild cognitive impairment ( MCI ) . The proportion of verbal information retained after a delay period was the planned primary outcome measure . Secondary outcome measures included attention , caregiver rating of functional status , and plasma levels of insulin , glucose , beta-amyloid , and cortisol . METHODS Twenty-five participants were r and omly assigned to receive either placebo ( n = 12 ) or 20 IU BID intranasal insulin treatment ( n = 13 ) using an electronic atomizer , and 24 participants completed the study . Participants , caregivers , and all clinical evaluators were blinded to treatment assignment . Cognitive measures and blood were obtained at baseline and after 21 days of treatment . RESULTS Fasting plasma glucose and insulin were unchanged with treatment . The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group ( p = 0.0374 ) . Insulin-treated subjects also showed improved attention ( p = 0.0108 ) and functional status ( p = 0.0410 ) . Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide ( A beta 40 ; p = 0.0471 ) without affecting the longer isoform ( A beta 42 ) , result ing in an increased A beta 40/42 ratio ( p = 0.0207 ) . CONCLUSIONS The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease , and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders 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 
    Output:
    
Most studies showed that verbal memory and especially story recall was improved after IN insulin administration .
Sometimes the effect was restricted for apoe4 ( − ) patients .
Intranasal insulin did not affect other cognitive functions .
However , there were some positive results in functional status and daily activity .
Conclusions Intranasal insulin  improved story recall performance of apoe4 ( − ) patients with AD or MCI .
Other cognitive functions were not affected , but there were some positive results in functional status and daily activity .