just how far back in time should one go when searching data of vascular dementia ( vad ) ? in 1549 , jason pratensis published de cerebri morbi , linking dementia to stroke , and in 1658 , johann jakof wepfer theorized that a broken brain blood vessel may cause apoplexy ( stroke ) .
the correlation between atherosclerotic disease and dementia was clearly identified only at the beginning of the 20th century by two well - known contributors to the field of neurodegeneration : alois alzheimer and otto binswanger .
the modern era of vascular dementia began in the 1960s , under the leadership of the newcastle college of medicine .
the concept of vad was ever since under permanent scrutiny and revision , in light of new clinical , pathological , and imagery data ( figure 1 ) . in the
early 1970 's , multiple infarct dementia was recognized as a major type of dementia , apart from alzheimer 's disease , characterized not by  neuronal atrophy  but by atherosclerotic burden . in 1975 , vladimir hachinski defined the  ischemic score ,  later used for the clinical diagnostic of vascular dementias .
however , the concept of vad soon became controversial due to an increased discrepancy between the incidence of cognitive disorders and that of the  strategic stroke .  furthermore , the early prevention of multi - infarct dementia ( mid ) , the aging of the general population , and an arising need to define  normal aging  versus  pathological aging    added to this controversy . the struggle to identify preventable and treatable factors widened the pathogenic spectrum of vad .
several epidemiological studies reported associations of hypertension , type 2 diabetes , obesity , and inflammation with vad and , in some cases , ad .
these all coincide with those of stroke , which in turn is an established factor for cognitive decline and vad   and underlines furthermore   the need for a new classification of dementia types . during the last two decades
, there was a switch of exploration from classical pathology to new imaging techniques at the molecular level .
therefore , new pathogenic pathways were identified , which greatly increased the complexity of mechanisms of neuronal loss due to cerebral vascular injury . in each stage of clinical and imaging research , new attempts were made to define vad as an individual , self - standing class of dementia .
mayer - gross et al . presented in the late 60s a set a criteria including dementia with focal signs and symptoms consistent with stroke , a fluctuating course , preservation of intellectual powers , and personality until late in the disease .
the  multi - infarct dementia  ( mid ) , first described by vladimir hachinski , was characterized by a number of small ischemic strokes that may not result in focal neurologic deficits , but in time , by cumulative damage , would lead to cognitive decline .
later , the hachinski ischemic scale , used for mid diagnosis , was modified by loeb and gandolfo to include ct scan criteria . in the 1990s , as acknowledgment of overlapping features of various types of dementia , vad criteria included clinical and imaging features of probable and possible disease .
currently , the most widely used criteria for vad include the diagnostic and statistical manual of mental disorders ( dsm ) , alzheimer 's disease diagnostic and treatment centers ( addtc ) , international statistical   classification of diseases ( icd ) , and national institute of neurological disorders and stroke  association internationale pour la recherche et l'enseignement en neurosciences ( ninds - airen ) criteria .
the concept of brain ageing stated at first that cell death might be responsible for the progressive deterioration of different physiological functions .
studies on aged animals   from over two decades ago reported neuronal loss with aging , with or without cortical thinning ( depending on the type of method used for quantification ) , but with diminution of the total volume of gray matter . by the end of the 1980s ,
reports of preserved neuronal number , despite cortical thinning in human brain , started to challenge the previous data and were followed by confirmatory studies on animals [ 1720 ] .
this controversy was solved by modern imaging investigational methods , starting with computer tomographic analysis in the early 1980 's   and continuing with recent pet and mri analyses [ 22 , 23 ] .
these techniques demonstrated that brain atrophy does occur with age in the healthy , nondemented elderly , involving both gray and white matter , but the loss is rather of neuronal connections , not of neurons .
furthermore , quantitation of neurons showed that , despite frontal and medial temporal cortical thinning , the number of neurons is preserved in healthy adults .
reported that , in frontal and temporal neocortical regions , the neuronal count remained relatively constant over a 50-year age range , suggesting that the atrophy is a reflection of the 3d neuronal network loosening rather than perikaryal loss .
the prefrontal cortical neurons seem to be particularly vulnerable to ageing , as a decrease in dendritic branching has been reported in neocortex of both rat   and human brains [ 2628 ] . by contrast , there is no significant change in dendritic length of hippocampal granule cells , nor a reduction in spine density in the dentate gyrus of aged humans   or rats .
white matter reduction is also a consistent finding in the aged human brain , possibly as an indicator of defective myelination ( although oligodendrocyte number seems to increase ) .
white matter loss is strongly correlated with vascular risk factors , particularly hypertension and stroke , two pathologies included in the broad spectrum of vad risk factors .
however , the involvement of white matter abnormalities and the presence of lacunae yielded contradictory results in terms of functional integrity and cognitive impairment .   at the molecular level , aging is a  decrease in homeostatic reserve    which interferes with neuronal ability to limit and buffer the increase of reactive oxygen species ( ros ) production , to sustain a protective response to cytotoxic stimuli or to limit vicious cycles such as inflammatory environments .
dna damage increases with age ( some of which is ros related ) , somatic mutation in human lymphocytes being nine times more frequent in aged human subjects than in neonates , and mitochondrial dna being even more sensitive than nuclear dna .
mitochondrial aging brings its share of vulnerability to stress in aged cells , with decreased atp reserves   along with affected cellular calcium removal systems and low buffering capacity .
moreover , one should take into account the fact that , in the brain , these processes affect , at different rates , different cell types that share a homeostatic balance . on the other hand , understanding aging of the nervous tissue , as compared to other tissues , could be a more challenging task due to a more complex regulation , signaling , and intercellular interactions .
the molecular perspective on vad is rather limited ; the general concept of this type of cognitive impairment has derived from clinical and imaging findings and is correlated , at the cellular level , with neuronal death and the sudden interruption of neuronal networks .
the main pathological changes leading to different forms of vascular dementia take place in both large ( atherosclerosis and thrombosis ) and small ( lipohyalinosis and fibrosis ) cerebral vessels , secondary to common vascular risk factors , such as hypertension , diabetes mellitus , and dyslipidemia .
the reduction in cerebral blood flow ( cbf ) starts early during vascular disease   and , therefore , a major vascular event can be preceded by a variable period of chronic hypoxia . as a result , the brain cellular microenvironment might change and adaptive processes may lead to cellular malfunction , rather than cellular death .
normal aging is associated with low cerebral flow and velocity at rest   and an attenuation of responsivity to hypoxia , hypercapnia , or blood pressure alterations .
these modifications may appear due to either histological alterations of the vessel wall ( thickening of basement membrane , loss of pericytes , and an overall reduction in cortical vascular bed ) or lower metabolic demand .
the same changes in blood flow , but at a higher rate , were documented in subcortical ischemic vad patients by pet studies , with some groups reporting a preferential decrease in frontal lobe regions . in laboratory rats ,
chronic hypoxia increases the cbf for several days , after which a decrease towards the baseline is noted , probably due to compensatory mechanisms such as increased hematocrit and decreased metabolic needs .
hypoxia inducible factor-1 ( hif-1 ) was used by ritz et al . as a marker of hypoxia in the cortex of young ( 2 months ) and
old ( 9 months ) spontaneously hypertensive rats ( shr ) and stroke - prone shr , in their study on hypoxic alterations of nonneuronal populations .
interestingly , the increase in hif1 was documented only in aged animals , along with an imbalance between microvessels and astrocytes at the level of the neurovascular unit . in hypoxic conditions
, hif-1 is upregulated , dimerizes with hif-1 ( the constitutively expressed subunit of hif-1 ) , translocates into the nucleus , and binds to hypoxia - responsive elements ( hres ) of target genes , such as vascular endothelial growth factor ( vegf ) , glucose transporter-1 ( glut1 ) , lactate dehydrogenase ( ldh ) , erythropoietin ( epo ) , and nitric oxide synthase ( nos ) .
endothelial malfunction is considered to be a first step in the development of atherosclerosis , and may be objectified by overexpression of inflammatory cytokines and adhesion molecules , leading to monocyte recruitment in the nascent atherosclerotic plaque and overproduction of reactive oxygen species ( ros ) , as a sign of mitochondrial , peroxisomal , and lysosomal alteration .
measurements of plasma markers in vad patients showed increased levels of proinflammatory cytokines ( il1 , il6 , tnf ) as well as anti - inflammatory cytokines ( il-10 ) .
il-6 and tnf levels increase with aging in animals and humans , and il-6 transgenic mice also show progressive proliferative cerebellar angiopathy and blood - barrier ( bbb ) breakdown .
these events indicate the endothelium as one of the main targets of proinflammatory cytokine il-6 .
the same transgenic strains indicated for the first time a causative relationship between local production of il-6 in the brain and the age - related decline in learning and cognitive function , demonstrating dendritic vacuolization , stripping of dendritic spines , decreased synaptic density , and loss of gaba - producing neurons in the hippocampus . in association with neurodegenerative changes ,
a diffuse nonproliferative gliosis with marked activation of astrocytes and microglia was identified in gfap - il6 mice .
furthermore , studies in transgenic mice overexpressing tnf and/or its receptors ( p55 and p75 ) demonstrated that il-6 is a potent microglial activator and , depending on the receptor it activates , ( i ) an endothelial activator ( via p75 ) , leading to increased expression of adhesion molecules , bbb disruption , and cns leukocyte infiltration or ( ii ) a demyelinating agent and oligodendrocyte apoptosis inducer via p55 . according   to batti and o'connor , although tnf has no effect on synaptic transmission or long - term potentation ( ltp ) under basal conditions , it severely impairs the recovery of postsynaptic transmission after hypoxic exposure .
they also showed that the tnf effect is p38/mapk mediated , a signaling pathway involved as well in hypoxic neuronal death in the ca1 region of the hippocampus .
but , in addition to its neurotoxic nature , tnf may also exert neuroprotective effects [ 48 , 49 ] in selected signaling contexts .
suggested to be another marker of chronic inflammation , e - selectin is an endothelial adhesion molecule , that is involved in weak linking of circulating leukocytes .
its expression is upregulated by il-1 and tnf. elevated levels of e - selectin have been previously linked to experimental and clinical brain ischemia , and high levels of soluble selectin ( se - selectin ) have been correlated with severe cerebrovascular disease .
generating immune tolerance against e selectin by repeated low - dose mucosal administration in lab rats had a protective effect against hemorrhagic strokes in hrs rats and against vci development in wistar rats , as shown by wakita et al . .
the impact of ros on cognitive function is elegantly demonstrated by studies of superoxide dismutase ( sod ) isoenzyme transgenic mice .
overexpression of mitochondrial sod has a neuroprotective role against drug - induced neurotoxicity , overexpression of cytoplasmic   sod improves age - related impairments in ltp , and overexpression of extracellular sod is correlated with better spatial memory in laboratory rats .
following cerebral ischemia , the production of free radicals was increased in aged rats and human endothelial cells , mainly by overproduction in the monocyte / macrophage system , especially when stimulated by inflammatory mediators .
hypoxia is associated with increased expression of all no synthase isoforms , including neuronal ( nnos ) , astrocyte and microglia - inducible isoform ( inos ) , and endothelial isoform ( enos ) , which are involved in neuronal death through inhibition of mitochondrial respiration and nmda / ca - induced exotoxicity [ 56 , 57 ] .
brain cells are particularly sensitive to ros aggression due to their high content of polyunsaturated fatty acids , which constitute a substrate for lipid peroxidation .
exposure of brain cells to oxidative stress increases the accumulation of cholesterol in cell membranes , leading to decreased fluidity and impaired transmembrane transport .
hypoxia also upregulates the expression of bdnf  a neurotrophic factor with important roles in neuroplasticity and hippocampus - related learning .
this might serve as a protective mechanism against a paucity of hippocampal bdnf mrna and bdnf plasma levels at older ages .
bdnf is further reduced by vascular risk factors such as hypertension and poor glucose metabolism . however , hypoxic upregulation of bdnf is not accompanied by upregulation of its high - affinity receptor trk - b , but of its low - affinity receptor p75 , a tnf superfamily receptor . the p75 expression is upregulated by hypoxic conditions and is correlated with an increase in caspase-3 activation in cortical and hippocampal neurons , leading to apoptosis .
the upregulation of p75 is linked to nos stimulation and to ca - mediated regulation of expression , suggesting a complex transformation of the pattern of molecular expression in chronic ischemia and vad .
   mixed  dementia is , by the very definition of vladimir hachinski himself , 
alzheimer 's disease and cerebral infarcts contributing to the dementia  , but other coexisting pathologies are also common in dementia such as parkinson disease ( in about 20% of patients with ad ) and   dementia with lewy bodies ( up to 50% ) .  
many data suggest that  pure  vascular dementia is rare and is the exception , rather than the rule [ 6365 ] .
vasculopathy as a trigger of ad neuropathological features has been proposed repeatedly before [ 6668 ] , and it is very likely that a patient with late - onset ad may already have a vascular burden and shares with vad vascular risk factors .
moreover , zhang et al . demonstrated that the low - oxygen dependent increase in hif1 expression was accompanied by an increase of bace1 protein levels and a secondary increase in a production .
these data suggest that restoration of normal oxygen levels to hypoxic tissues , for example , by the use of small molecules that lower the affinity of oxygen for hemoglobin , could be an interesting issue for research [ 70 , 71 ] .  
activation of inflammation is a consistent finding in ad , as shown in cell culture models [ 72 , 73 ] , animal models [ 74 , 75 ] , and postmortem studies on ad brains [ 7678 ] .  
inflammation was related to the onset of cognitive decline and also correlated with disease progression by measurements of serum tnf and the tnf/il1- ratio .
patients with ad show elevated levels of tgf- that are correlated with low expression of tgf - r in the affected brain areas , especially around cerebral vessels with caa .
furthermore , inflammation is associated with ros production , and oxidative stress has a dual relationship with a peptide : ( i ) it favors the aggregation of a into a fibrillar form and ( ii ) it mediates the toxic effect of a on neuronal cells , as shown by the protective effect of antioxidants and free radical scavengers . in turn , some a peptides ( such as the 2535 form ) have an intrinsic lipoperoxidizing effect , as established on neocortex - derived synaptosomes .
oxidative stress is demonstrated by the increased amount of 4-hydroxynonenal ( hne ) , which was shown to interfere with plasmalemmal atpases and transporters , including ca shifters , further increasing metabolic imbalance in ad .  
downstream a production and accumulation results in secondary endothelial malfunction through : ( i ) amyloid angiopathy ; ( ii ) nos inhibition ; ( iii ) atherogenesis correlated with endothelial activation and overexpression of inflammatory cytokines and adhesion molecules ,   even before a deposition ;   ( iv ) lipid peroxidation in the frontal cortex in ad brains ; ( v ) bbb alteration . to conclude
, there is an overlap of events between chronic hypoxia and ad on several levels , such as hypoxic - triggered cellular pathways , inflammatory environment , growth factor signalling , and calcium homeostasis ( figure 2 ) .
thus , from the molecular level perspective , the diagnostic criteria for neurodegenerative diseases have become ill defined or insufficient and there is a true need for redefinition .
normal aging and various types of neurodegeneration share common molecular events ( table 1 ) , such as alteration of cerebral blood flow , neuroinflammatory environment , and endothelial malfunction .
aging has also been associated , at the cellular level , with increased production of reactive oxygen species ( ros ) .
oxidative alteration of enzymes and the subsequent loss of enzymatic activity is a trait of the aging brain , particularly , in the anterior frontal lobe .
oxidative stress leads to the accumulation of free cholesterol , along with ceramides , lipid peroxides , and derived aldehydes ( such as hne ) , that covalently bind to membrane proteins , altering their functions .
oxidative stress is involved as well in the disruption of ca homeostasis , an effect studied especially in neurons , where ca is a vital mediator of neuronal signaling .
it appears that , in aged neurons , several ca homeostatic systems are affected   and there is impairment in the maintenance of a nontoxic ca overload .  
although it seems that levels of nnos and enos do not change with age , still there is an increase in nos activity in aged rat cortex .
these two nos isoforms are ca induced , which correlates with the above - mentioned impairment of aged cells to deal with ca overload .
furthermore , consistent with the ca - independent nature of inos , there are several reports underlining its absence in the normal aged cortex of lab rats [ 15 , 60 , 105 ] .
instead of considering vad a pure result of neuronal death and the interruption of neuronal networks that support cognitive function , we hypothesize that early brain malfunction is induced by vascular risk factors and chronic hypoxia .
a reduction of cbf and a series of molecular events precede the major ischemic events in vascular cognitive impairment . based on these subtle changes , intervention at early stages
could prevent the full - blown development of dementia , which might represent a  point of no return  for the neurovascular units and neuronal networks with few chances for effective treatment .
 vascular dementia is , in its current conceptual form , a distinct type of dementia with a spectrum of specific clinical and pathophysiological features . 
 however , in a very large majority of cases , these alterations occur in an already aged brain , characterized by a milieu of cellular and molecular events common for different neurodegenerative diseases . 
 the cell signaling defects and molecular dyshomeostasis might lead to neuronal malfunction prior to the death of neurons and the alteration of neuronal networks . in the present paper 
 , we explore some of the molecular mechanisms underlying brain malfunction triggered by cerebrovascular disease and risk factors . 
 we suggest that , in the age of genetic investigation and molecular diagnosis , the concept of vascular dementia needs a new approach . 
1. Vascular DementiaHistorical  Considerations
2. The Concept of Brain Ageing
3. VaD from a Molecular Perspective
4. Mixed versus Pure Dementia
5. Overlapping of Normal Aging and Neurodegenerative Diseases at Cellular and Molecular Level
6. Conclusions