dementia represents a considerable public health issue in developed countries due to progressive increase of affected individuals occurring with rapid ageing of population [ 13 ] . actually , high blood pressure ( bp ) is one of the most important factors negatively affecting the modalities of cerebral aging [ 24 ] . cerebral damage is mediated by changes in cerebral vasculature affecting both large and small vessels : the macrovascular atherosclerotic disease causes brain infarcts ( either clinically evident as stroke , or silent ) , the microvascular disease results in chronic ischaemic changes affecting the white matter to a large extent [ 5 , 6 ] . the outcome of single or multiple events is a stepwise progression to multi - infarct dementia , and that of chronic microvascular damage is a continuous progression from mild cognitive alterations to overt vascular dementia [ 5 , 6 ] . the right approach to this problem is to place emphasis on preventive strategies to identify and counterbalance the risk factors at a population level . although hypoperfusion and neurodegeneration have emerged as possible underlying mechanisms , the pathophysiology of the relationship between high bp and low cognition remains unclear . not only this , but also the bp levels that should be targeted to achieve optimal perfusion while preventing cognitive decline are still being debated [ 36 ] . furthermore , it is uncertain if , to preserve cognition , it is better to keep low systolic bp , diastolic bp , or both . the aim of the present study is to investigate the relationships of the different components of bp with cognitive function and cognitive reserve in a representative sample of general population and to identify the domains most affected . all men and women aged 50 years living in two italian towns were invited by letter for a screening ; 1,377 ( 76% ) agreed with the study protocol , gave informed consent , and were recruited and regularly followed up ; 288 randomly selected subjects ( 164 men and 124 women ) underwent the neuropsychological tests described below and were considered for the analysis of data in the present work . their general characteristics did not differ significantly from those of the remaining part of the sample ( data not shown ) . the study subjects , whose general characteristics are shown in table 1 , were seen by a staff of specialists at an ad hoc hospital unit , received a rose 's questionnaire about clinical history , smoking habits , and lifestyle , and underwent bp measurements in triplicate by trained medical doctors by means of an automatic 705 it device ( omron europe , hoofddorp , netherlands ) ; the average of the last two measurements was taken into account for the analysis of data , and every effort was made to avoid terminal digit preference . pulse pressure ( pp ) cognitive assessment was performed by means of mini - mental state examination ( mmse )   and a comprehensive neuropsychological battery of validated tests  paper and pencil short - term memory was studied by means of digit span , long - term memory by means of immediate and delayed prose memory , and working memory with interference at 10 seconds . the executive functions were explored using memory with interference at 30 seconds , the trail making test b , the phonemic verbal fluency test , and the clock drawing test . attention was studied by means of the trail making test a   and of the overlapping figures . the entire battery of tests was administered in a single session which took approximately two hours to complete . the digit span   consisted of memorization and repetition of a series of numbers . in immediate and delayed prose memory , a prose passage containing 30 words was presented to each participant on a one - to - one basis ; immediate verbatim recalls were assessed , followed by a 10-minute delayed verbatim recall . in the tests of memory with interference at 10 and 30 seconds ( mi 10 and mi 30 , resp . ) , the participants were requested to recall a consonant trigram after an interval delays during which they had to count backward starting from a 3-digit random number presented by the examiner immediately after the trigram . phonemic verbal fluency   required participants to generate appropriate names in a fixed period of time . in the trail making test a ( tmt - a ) , subjects were required to connect with line progressive numbers , and in the tmt - b progressive numbers and letters . in the clock drawing test ( clox ) , the participant was instructed to draw a clock indicating 2  :  45  h , setting the hands and numbers on the face  so that a child could read them  . the entire battery of tests was administered in a single session which took approximately 2 hours to complete . the results of the neuropsychological battery were compared to the normative sample for italian subjects aged 50 years . this sample was also used to produce individual normal values for each test and to stratify subjects into those showing normal and impaired cognitive function . cognitive reserve index ( cri)the ability to optimize and maximize performance through recruitment of brain networks and/or compensation by alternative cognitive strategies was also measured through a validated questionnaire   to explore the difference between individuals in their capacity to cope with or compensate for pathology . the label of arterial hypertension   required systolic blood pressure 140  mmhg or diastolic blood pressure 90  mmhg or history of hypertension or appropriate antihypertensive treatment or hospital discharge with diagnosis - related group ( drg ) 401404 or 4020040290 or 4030040391 . body mass index ( bmi ) was calculated as the weight / squared height ratio , and obesity was defined as bmi 30  kg / m . truncal obesity was defined as suprailiac / triceps skinfold 2.24 in men or 1.32 in women . left ventricular hypertrophy required a left ventricular mass index 125  g / m in men or 110  g / m in women . subjects were labelled as diabetic when having fasting blood glucose repeatedly 126  mg / dl , blood glucose 140  mg / dl two hours after 75  g oral glucose , blood glucose 200  mg / dl at casual measurement , or current antidiabetic treatment confirmed by general practitioner . as a measure of insulin resistance , the homeostasis model assessment index   was calculated from homa - r = ( circulating insulin in u / ml )  ( fasting blood glucose in mmol / l)/22.5 . history was positive for coronary artery disease when the minnesota code was 1.2 , 1.2 , or 1.3 if absent 6.4.1 , or 4.1 or 4.4 if absent 6.4.1 , 7.1.1 , and 7.2.1 , or 5.1 , 5.2 , 5.3 , or 5.4 if absent 6.4.1 , 7.7.1 , 7.2.1 , and 7.4 , or akinesia or dyskinesia were present at echocardiogram , or in the presence of positive myocardial scintigraphy or stress test , or of positive history of myocardial infarction or angina pectoris confirmed by hospital files , or in chronic appropriate antianginal treatment , or in the presence of hospital discharge with diagnosis - related group 410414 . history was positive for cerebrovascular disease when in the presence of neurological signs , on positive history of stroke or transient ischaemic attack , or positive tc or mr or on hospital discharge with drg 430438 . mmse was defined as low when scoring < 24 , mi-10 , and clox when below the first tertile . continuous variables were expressed as mean and standard deviation and compared with analysis of variance and the post hoc bonferroni 's correction . categorical variables were expressed as percent rates and compared with the pearson 's  test . multivariate regression analysis was used to identify the variables having a prognostic role on cognitive decline . the label of  hypertension  was first used to stratify subjects , and the two categories ( normotensive , hypertensive ) were compared . the systolic and diastolic bp components were then used as independent variables in multivariate regression analyses having the test scores as dependent . finally , as a unitary representation of the systolic and diastolic components , gender , age , bmi , historical cerebrovascular , and coronary events , education , arterial hypertension , diabetes , and antihypertensive treatment were used as covariables in multivariate analysis . finally , the joint distribution of mean systolic and diastolic bp was evaluated by bp vector analysis ( mean vector with 95% confidence intervals ) in subjects having normal or impaired test performance . this method has been described elsewhere [ 2326 ] and is detailed in the appendix . the investigation met the principles outlined in the declaration of helsinki and institutional guidelines and was approved by the local ethics committee . before the study and after consulting his / her own general practitioner , each subject accepted and signed an informed consent . men represented 43% of the cohort , and age at examination was 73.5  10.1 years ( range 53 to 94 ) . years of education were on average 6.2  2.6 ( range 2 to 18 ) . the scores of neuropsychological tests were not different from those expected for a normal group of reference persons of the same age . in multiple regression analysis , prose memory , memory with interference , and executive function were also positively related with education ( table 2 ) . 4after stratifying subjects according to the esh / who label of hypertension   ( table 3 ) , mmse score was 6.2% lower in the hypertensives than in the normotensives . after adjustment for age and education , mi-10 and clox were performed less efficiently ( 26% and 28% , resp . ) in the former than in the latter . the other tests were carried out with comparable performance in the two groups . in multiple regression analysis adjusted for age and education , both systolic bp and pp resulted to be independent predictors of mmse , with mi-10 and clox , while the diastolic component taken alone did not ( table 4 ) . when systolic and diastolic bps were analyzed together with bivariate vector analysis , the 95% confidence ellipses of the mean of the pair of variables  systolic bp ; diastolic bp  obtained from subjects showing low mmse , mi-10 and clox did not overlap ( p nonsignificant ) with those obtained from subjects showing normal performance ; subjects with impairment were displaced towards higher systolic and higher diastolic bp values ( arrow in figure 1 ) . cri was 6% lower in the hypertensives than in the normotensives ( table 3 ) and inversely predicted by pp in multiple regression model adjusted for age and education ( table 4 ) . in bivariate vector analysis , the bp vector of impaired cri was directed towards significantly higher values of systolic and lower values of diastolic bp ( figure 2 ) , that is , higher values of pp . high bp is known to be a risk factor for cognitive decline , and many studies demonstrated a relationship between bp levels and cognitive impairment [ 2730 ] . this association was confirmed in the present study , where high bp contributed to cognitive decline in a representative sample of general population of men and women . in our experience , this decline in subjects who were labeled as  hypertensive  according to current guidelines was not indiscriminate , but limited to working memory , executive functions , and global performance , while attention , language , visuospatial , and processing speed abilities were not affected . according to other authors , the systolic component of bp was associated to cognitive decline , while high diastolic bp per se was not and only acted as a factor able to increase the detrimental effect of high systolic values . in fact , diastolic bp was not an independent predictor in multivariate analysis , but ( at least for the three tests shown in figure 1 ) the bp vector of cognitive impairment was directed towards higher values of both systolic and diastolic . the reasons of the association between arterial hypertension and impaired cognition are not completely understood , even though knowledge in this field is increasing . it is established that high bp causes directly or indirectly cerebral vascular damage ( mainly via atherosclerosis in the larger vessels and oxidative stress in vascular wall ) and is also responsible for structural alterations in small - caliber vessels ( particularly in the perforating arteries irrigating the cerebral white matter ) . the macrovascular disease due to chronically high bp causes brain infarcts ; the microvascular disease is associated to chronic ischaemic changes affecting the white matter and leading to multi - infarct dementia . not only this , but also it has been suggested that the vascular lesions accompanying high bp have a permissive effect on the clinical expression of alzheimer 's disease . in our experience , the idea of a reserve against brain damage comes from the observation that the relationship between brain damage degree and clinical manifestation is not linear . the cognitive reserve model suggests that the brain actively attempts coping with brain damage by using preexisting cognitive processing approaches or by enlisting compensatory approaches . for this reason , a given brain damage can have different effects on different subjects , and individuals can sustain considerable brain damage before showing functional deficit . our impression is that high systolic and low diastolic bp have to coexist before the cognitive reserve becomes impaired . in fact , in our experience , cri correlated inversely with pp , but not with systolic or diastolic bp taken separately . furthermore , when systolic and diastolic were considered as a whole , the bp vector of lower values of cri was directed towards higher systolic and lower diastolic , indicating that higher pp actually had a detrimental role on cognitive reserve greater than the systolic and diastolic components taken separately ; + 6  mmhg systolic and 1  mmhg diastolic were sufficient to stratify subjects into having lower or higher cri . in conclusion , our study contributes to the belief that a link exists between bp and cognition , higher values of systolic bp being associated to impaired cognitive function . although high bp is not sufficient per se to reduce cognitive performance , higher values of diastolic bp are counterproductive in subjects with high systolic . this effect is not indiscriminate but limited to a set of functions and is probably mediated by impairment of vascular reserve and microvascular disease . measures aimed at reducing or keeping low bp ( particularly systolic bp ) are mandatory in middle age to keep good cognitive abilities in late life . this underscores a need to consider pharmacological and nonpharmacological interventions to control arterial stiffening and maintain arterial compliance . this study is novel in that it highlights the accessory role of diastolic in addition to systolic bp in modulating cognitive functions at a population level . not only this , but also it clarifies that the cognitive decline accompanying high bp is not indiscriminate , but limited to memory and executive functions . finally , it introduces in the estimation of cognitive decline an innovative concept , that of cri , that seems to be particularly affected by pulse pressure .
in 288 men and women from general population in a cross - sectional survey , all neuropsychological tests were negatively associated with age ; memory and executive function were also positively related with education . 
 the hypertensives ( ht ) were less efficient than the normotensives ( nt ) in the test of memory with interference at 10 sec ( mi-10 ) ( 33% , p = 0.03 ) , clock drawing test ( clox ) ( 28% , p < 0.01 ) , and mini - mental state examination ( mmse ) ( 6% , p = 0.02 ) . lower mmse , mi-10 , and clox were predicted by higher systolic ( odds ratio , or , 0.97 , p = 0.02 ; or 0.98 , p < 0.005 ; or 0.95 , p < 0.001 ) and higher pulse blood pressure ( bp ) ( or 0.97 , p = 0.02 ; or 0.97 , p < 0.01 ; and 0.95 , p < 0.0001 ) . 
 the cognitive reserve index ( cri ) was 6% lower in the ht ( p = 0.03 ) and was predicted by higher pulse bp ( or 0.82 , p < 0.001 ) . 
 the bp vectors of lower mmse , mi-10 , and clox were directed towards higher values of systolic and diastolic bp , that of low cri towards higher systolic and lower diastolic . 
 the label of hypertension and higher values of systolic or pulse bp are associated to worse memory and executive functions . 
 higher diastolic bp , although insufficient to impair cognition , strengthens this association . 
 cri is predicted by higher systolic bp associated to lower diastolic bp .