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Vascular mechanisms are increasingly recognized as a contributing factor to dementia in the elderly
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Vascular dementia generally reflects a heterogeneity in terms of presentation related to the varying distributions of vascular involvement
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Small vessel ischemic disease overlaps with both vascular and neurodegenerative dementia and has become an increasing focus of study
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Hemorrhagic stroke is often associated with clinically significant cognitive deficit although its contribution to the spectrum of vascular dementia tends to be less emphasized
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Identification of vascular cognitive impairment, preceding actual vascular dementia, may allow initiation of interventions with potential for halting or delaying progression of the cognitive deficit
Abstract
Objective
Vascular dementia (VaD) is the second most common cause of dementia and a major health concern worldwide. A comprehensive review on VaD is warranted for better understanding and guidance for the practitioner. We provide an updated overview of the epidemiology, pathophysiological mechanisms, neuroimaging patterns as well as current diagnostic and therapeutic approaches.
Materials and methods
A narrative review of current literature in VaD was performed based on publications from the database of PubMed, Scopus and Google Scholar up to January, 2021.
Results
VaD can be the result of ischemic or hemorrhagic tissue injury in a particular region of the brain which translates into clinically significant cognitive impairment. For example, a cerebral infarct in the speech area of the dominant hemisphere would translate into clinically significant impairment as would involvement of projection pathways such as the arcuate fasciculus. Specific involvement of the angular gyrus of the dominant hemisphere, with resultant Gerstman's syndrome, could have a pronounced effect on functional ability despite being termed a “minor stroke”. Small vessel cerebrovascular disease can have a cumulate effect on cognitive function over time. It is unfortunately well recognized that “good” functional recovery in acute ischemic or haemorrhagic stroke, including subarachnoid haemorrhage, does not necessarily translate into good cognitive recovery. The victim may often be left unable to have gainful employment, drive a car safely or handle their affairs independently.
Conclusions
This review should serve as a compendium of updated information on VaD and provide guidance in terms of newer diagnostic and potential therapeutic approaches.
is a neurocognitive disorder that represents clinically significant cognitive impairment directly related to vascular injury to the brain with a number of potential contributing factors recognized (Fig. 1). Of note, from a mechanistic standpoint, the development of vascular-mediated cognitive impairment reflects specific areas of cognitive domain involvement. The resultant clinical picture can result from either localized larger vascular territory injury or cumulative cerebral small vessel disease (SVD). VaD is generally viewed as the second most common cause of age-related dementia. The pathogenesis is attributed to vascular causes in the absence of other pathologies.
It accounts for roughly 20% of all dementia with the prevalence tending to parallel stroke risk. Reflective of evolving concepts in the dementia realm, the Fifth Edition of the Diagnostic and Statistical Manual (DSM-V) criteria has replaced the term “vascular dementia” with “vascular neurocognitive disorder”.
Historically, VaD was previously referred to multi-infarct dementia reflective of the view that cumulative tissue loss, related to recurrent ischemic stroke, was the primary mechanism. Based upon pathological findings, it was felt that 50 to 100 mL of tissue loss would translate into dementia.
reviewed various criteria, and based upon their analysis, they concluded that the criteria of the state of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and the NINDS-AIREN criteria were the only ones of clinical utility. The various scales that have been developed are generally based upon a stroke-like presentation, with resultant cognitive impairment temporally related to the ictus, along with supportive neuroimaging findings and risk factors for stroke and these include the Hackinski Ischemic Scale,
By these criteria, “dementia” is defined as decline in memory and impairment of two other intellectual domains which interfere with daily activities of individual. There should be clinical signs of stroke, from the history and examination, presumptive risk factors for stroke, along with neuroimaging support and with dementia identified within 3 to 6 months of the event, In the absence of a history of stroke, there should be subtle focal neurological signs to support a cerebrovascular mechanism. However, these various criteria have primarily been proposed for research purposes and the definitive diagnosis of VaD needs confirmation neuropathologically to rule out a significant neurodegenerative component to the dementia.
Various terminologies have evolved in recognition of the various mechanisms of VaD including both large vessel and small vessel (Table 1). Otto Binswanger, for example, described a subcortical arteriosclerotic encephalopathy, which became known as Binswanger's disease,
and presumably translates into what now may be referred to as subcortical microvascular ischemia, cerebral small vessel disease (SVD), ischemic demyelination, leukoaraiosis or the “lacunar state”.
To reflect greater inclusiveness of the various mechanisms, including hemorrhagic stroke, the term Vascular Cognitive Impairment (VCI) has been proposed
where attention to new biomarkers, innovative cerebrospinal fluid results, genetic studies and advances in neuroimaging needs to be incorporated into evolving criteria. For example, cerebral positron emission tomography (PET) scanning with beta-amyloid and tau protein tracers is in the process of revolutionizing our approach toward potential therapies in AD. A Journal of the American College of Cardiology Expert Panel
proposed Major versus Minor VCI and subcategorized Major VCI into PSD developing within six months of the stroke with possible components of AD or Dementia with Lewy Bodies (DLB), Subcortical Ischemic Vascular Dementia, Multi-Infarct (Cortical) Dementia, and Mixed Dementia which could include VCI-AD and VCI-DLB. For the purposes of clarity and pragmatism, with this review, we will view VaD as clinically relevant cognitive impairment with the cerebrovascular insult as the primary mechanism. Despite the tremendous efforts to categorize and re-categorize diagnostic criteria for VaD, these efforts have not translated into effective therapies, to date, although stroke preventive measures have made significant inroads as will be discussed.
Formal cognitive testing can certainly be a fairly reliable indicator of VaD in patients with clinical support for this. However, it remains to be seen how practical such formal cognitive testing is when cooperation may be limited. In addition, aphasia as well as denial and neglect, could well impact the reliability, and practicality, of the testing and one must also address co-morbid factors such as medications that can affect cognitive performance as well as not infrequently seen post-stroke depression.
Functional scales may provide complementary information in terms of outcome following stroke such as the Modified Rankin scale or the Barthel Index which tend to provide more reliable information three months out from the ictus
which is the timeframe for which most patients will exhibit significant recovery if this is to occur. Table 2 summarizes factors which support the diagnosis of VaD.
Table 2Support for the diagnosis of vascular dementia.
Number
Criteria
1
Clinical presentation of stroke 3 to 6 months of onset
2
Neuro-imaging support of either macro-, lacunar or micro-infarction
3
Characteristics of cognitive deficit supportive of vascular etiology
4
Manifestations of stroke residua on exam
5
Risk factors of stroke
6
Clinical course compatible with maximal deficit at ictus followed by improvement
Naturally, the presence of the various risk factors for stroke, both ischemic and hemorrhagic, will impact significantly on the prevalence of VaD (Table 1). The prevalence of VaD will also be markedly impacted by the tools available and used to determine if VaD is the primary contributor to the dementia rather than a less important contributing factor. For example, if one is using magnetic resonance imaging (MRI) as the primary diagnostic support modality, in tandem with clinical features, then the availability of high quality scans with experienced readers is mandatory for accurate information. On the other hand, when there is data from underdeveloped countries, where the expertise and neuroimaging may be limited, it is not unexpected to have inaccuracies especially in the detection rate.
The use of relatively available and fairly readily applied cognitive screening tests will help in the detection of clinically significant cognitive compromise potentially on a global basis. In this regard, the Montreal Cognitive Assessment (MoCA) has be reported to be superior to the Mini-Mental State Exam (MMSE) for the determination of VaD
This may be reflective of its greater emphasis on attention and executive function than the MMSE. More comprehensive neuropsychological assessment is available and may be of particular value to determine potential work and driving capability.
The use of variable criteria for VaD in various parts of the globe may impact how well the prevalence and incidence are determined.
age-standardized prevalence estimates for VaD were determined to be 1.5% overall, with a range from 0.6% in 65-74 year olds, to 4.8% in those over the age of 85 years. The estimated annual incidence of VaD was found to be between 2.5-3.8 cases out of a thousand. It is estimated that 15 to 20% of dementia cases are attributable to VaD, in Europe and North America
Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the elderly research group.
Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group.
which is presumably directly related to their overall higher risk for stroke. Widespread drop in tobacco usage and improved compliance with well-established measures for stroke prevention in regards to hypertension, diabetes mellitus, hyperlipidemia and cardiac related factors, such as atrial fibrillation (AF), have presumably contributed to a decrease in VaD prevalence.
Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American heart association/american stroke association.
the incidence of dementia was observed to diminish from 3.6 per 100 persons in the late 1970’s to 2.0 per 100 persons by 2010. This was partly explained by reductions in dementia associated with stroke, AF and congestive heart failure (CHF) although the prevalence of diabetes mellitus and obesity were not observed to be diminished over this timeframe. Of particular pertinence, when addressing the overlap of dementia, VaD and AD share several common risk factors.
called attention to a white matter component to the neuropathology of AD in addition to the typical findings of beta-amyloid plaques, neurofibrillary tangles, granulovacuolar degeneneration and neuronal drop-out. It is not all unexpected that small vessel and large vessel ischemic insults, as well as systemic vascular factors, may contribute to the cumulative tissue impairment associated with various forms of dementia including AD.
As mentioned previously, the pathophysiological heterogeneity of VaD results in much greater variability in presentation than AD. In VaD, the cognitive impairment is dependent upon the location of vascular lesions and particular neural substrates affected by vascular pathology.
A not uncommon presentation of VaD is executive dysfunction featured as predominant deficits in attention, information processing, difficulties in complex activities, and disorganized thought and behaviour.
At the bedside, or clinic, the MMSE and MoCA are commonly used to assess for the presence of mild cognitive impairment (MCI) or actual dementia. The VADAS-cog is another assessment scale to assess for cognitive impairment at the bedside.
Comparison of the Alzheimer's disease assessment scale cognitive subscale and the vascular dementia assessment scale in differentiating elderly individuals with different degrees of white matter changes. The LADIS Study.
Significant neurological deficit from an acute macrovascular infarct or intracerebral haemorrhage (ICH), will impact what is feasible for cognitive assessment, particularly in the acute setting. Furthermore, as opposed to AD, where there is expected decline in cognitive function over time, the initial cognitive difficulty following the stroke is often expected to improve and then stabilize. Depression and apathy are not uncommon in VaD while hallucinations and delusions are less prominent.
reported the presence of such symptoms in 81.1% with apathy most frequent at 56.6%. One can also see post-stroke epilepsy, particularly with cortical infarcts or hemorrhages, which can impact the clinical course following the ictus.
Pathophysiology of vascular dementia
The pathophysiology of VaD was the subject of a comprehensive review by Kalaria.
It is generally noted that the pathology and clinical features of VaD is dependent on the mechanism of the stroke, degree of tissue loss, impact on connectivity of neural pathways, impact on exquisite regions of the brain vital for interaction with the environment
The potential molecular mechanisms contributing to the pathogenesis of cerebral infarction is illustrated in Fig. 2. As noted in the Fig., there has been increasing attention paid to the potential for inflammation to contribute to both atherosclerosis
The pathogenesis of VaD can originate from primary central nervous system vascular insult such as in situ thrombosis related to atherosclerosis, fibrinoid necrosis or lipohyalinosis which can overlap with some of the mechanisms related to hypertensive ICH. There can be vascular tear extravasation related to vascular anomaly rupture from a cerebral aneurysm or arteriovenous malformation (AVM). There can also be atypical vascular pathology such as vasculitis and vascular dissection. Extracranial mechanisms can include cardiovascular system-related hypoperfusion or embolic infarction from a cardiac source. Systemic factors can include connective tissue disorder, infectious etiologies, neoplastic mechanisms, hypercoagulable conditions, bleeding diatheses and polycythemia. In general, atherosclerosis tends to progress over time, with resultant vessel stenosis or occlusion, and is reflective of age as well as well as contributing risk factors such as hypertension, diabetes mellitus, hyperlipidemia, smoking and familial predisposition. Small vessel injury, such as lacunar infarction and other components of SVD, is most commonly associated with longstanding effects of hypertension on cerebral penetrating arteries resulting in progressive occlusive disease characterized by fibrinoid necrosis and lipohyalinosis. Such vessel pathology, including Charcot-Bouchard microaneurysms, also play a role in hypertensive ICH.
Macro-, or large vessel, infarction typically occurs in a particular vascular territory with the middle cerebral artery (MCA) most common in terms of presentation. The mechanism can be atherosclerotic stenosis with either critical impairment of the distal flow or actual large vessel occlusion (LVO). Alternatively, rupture of atherosclerotic plaque, thrombo-embolism, vascular dissection, arteriopathy, such as vasculitis or moyamoya disease, genetic mechanisms such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), haematological disorders such a pro-coagulant state, polycythemia or thrombocytosis, and cerebral hypoperfusion with borderzone infarction pattern, are other potential explanations. Generally speaking, roughly 50% of ischemic stroke is thrombo-embolic.
However, for a number of patients, the exact mechanism is never clearly determined. More esoteric causes, such as migraine, oral contraceptive use, vascular dissection and hypercoagulable conditions tend to be invoked in younger patients typically those less than 45 years of age without obvious risk factors for stroke. Embolic stroke of undetermined source (ESUS) is a designation for presumptive embolic stroke, clinically, without a source of the embolism readily identified.
both site of the lesions and severity are needed to diagnose VaD. These include large vessel strokes, strategically located stroke, old hemorrhages, multiple lacunar strokes in the basal ganglia, frontal lobe significant infarction or extensive white matter lesions. Severity includes large vessel strokes in the dominant hemisphere, or both hemispheres, and white matter lesions involving 25 % or more of the total white matter.
About 15% of VaD is associated with occlusion of extracranial arteries.
However, atherosclerosis is rare in small vessels, but can be seen in older patients with longstanding hypertension. Large strokes are identified by imaging on CT or MRI brain scan and may evolve clinically as VaD or mixed dementia.
The designation of "dementia” for acute large vascular territory insult can be somewhat problematic in terms of distinguishing cognitive versus physical impairment as the primary explanation for functional disability. Perhaps, from a practical standpoint, vascular or post-stroke dementia should be reserved for clinically significant cognitive impairment, directly related to a cerebrovascular insult, which leaves the person with cognitive impairment as the most functionally limiting sequela.
Cerebral Small Vessel Disease (SVD):
There is generally overlap between microinfaction, by definition only present on microscopic inspection with size ≤ 5 mm, and lacunar infarction which are ischemic cystic lesions < 1 cm in size. The cumulative findings are often referred to SVD which can also include cerebral microbleeds (CMBs), cortical superficial siderosis and prominent perivascular spaces (Table 3). SVD is associated with approximately 25% of ischemic stroke presentations.
Brain lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study.
Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.
The pathological overlap between VaD and AD underscores the challenges of effectively differentiating the two from both a mechanistic as well as potential therapeutic standpoint.
for example, in a study of presumptive VaD, reported that neuropathological findings supported AD as the primary mechanism for the dementia in 58% with significant contributions from both pathologies in 42%. Obviously, multiple large vessel infarctions, seen on brain scan, in a cognitively impaired individual will support VaD as the primary mechanism. On the other hand, the contribution of SVD to the dementia appears to be more subject to interpretation. This is, perhaps, in part, related to their microscopic nature which can impede detection and which has led them to be termed “invisible lesions”.
From a practical standpoint, one would expect the temporal pattern of large vessel infarction to be most pronounced, in terms of deficit, within several days of the ictus followed by some degree of recovery. With chronic SVD as the primary contributor, on the other hand, the relentless progression, more typical of AD, would tend to characterize the clinical course. In a community based study, Avanitakis et al
looked at microinfarction and its relationship to dementia in the Religious Orders Study. They reported microinfarcts in 129 of the 425 enrolled subjects (30%) and associated with an odds ratio of dementia of 1.77 with the risk correlating with the number of cortical microinfarcts. The cognitive deficit was most pronounced for semantic memory and perceptual speed.
There has been a literal explosion of information related to SVD. Much of this is related to enhanced imaging with MRI techniques which can identify, in an automated fashion, topographical distributions of WMH including statistical parametric mapping techniques.
Cumulative WMH has been termed “leukoaraiosis” which consists of variable degrees of demyelination, axonal loss, reactive astrocytes and macrophage, edema and microangiopathies of penetrating arteries.
reported that acute cortical microinfarcts, on high-resolution MRI, do not evolve into MRI detectable chronic microinfarcts. A number of imaging studies have focused on structural abnormalities associated with cerebral microangiopathies.
A Mayo Clinic Study of Aging found baseline hypertension, midlife hypertension and baseline fasting glucose, in males, were predictive of WMH progression with the relationship with hypertension stronger in females while metabolic syndrome was not associated with WMH progression.
microinfarcts were seen as a contributor in one-third. In a systematic review of neuropathological studies, involving 10,515 people, cerebral microinfarcts were seen in 62% with VaD, 43% with AD, 33% with combined pathology and 24% of non-demented older subjects.
Texture analysis of T1-weighted and fluid attenuation inversion recovery images detects abnormalities that correlated with cognitive decline in small vessel disease.
reported on the potential of an easily derived “simple” SVD score to predict the presence of dementia while a higher CSVD sum score, based upon WMH, lacunes, cerebral microbleeds and perivascular spaces, was associated with a higher risk for stroke, development of dementia and death in another MRI-based study
the prevalence of CMI was 62% in patients with VaD, 43% in AD and 24% in subjects ≥ 75 years of age without a diagnosis of dementia at autopsy. Some studies suggest that cerebral microinfarction is a marker of dementia in general with overlap between VaD and AD.
Three different modalities are of utility in the detection of cerebral microinfarction: (1) neuropathological exam (2) diffusion-weighted MR imaging and (3) high-resolution MRI and it is theorized that the associated functional impairment extends beyond the actual boundaries of the lesion.
In addition, there is clearly cumulative injury in most subjects which includes cerebral microinfarcts, cerebral microbleeds, lacunes, cortical superficial siderosis and MRI visible perivascular spaces.
The detection rate has been enhanced by MRI brain scan where they are seen in the subcortical regions with an axial diameter < 1.5 cm in the acute phase.
There has been refinement of efforts to standardize the imaging findings in an effort to enhance research efforts to document clinical consequences of their presence.
Standards for Reporting Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.
The pathophysiology reflects obstruction of penetrating brain arteries and arterioles resulting in deep small infarcts as well as fluid leakage associated with edema and subsequent gliosis in white matter tracts.
Typical “syndromes” such as pure motor and pure sensory stroke have been associated with their clinical presentation. They can be an important component of what has been termed “subcortical vascular dementia”.
reported that up to 30% of patients with lacunar infarct develop cognitive impairment within 4 years of the event. Impairment can include difficulty with executive function, attention and psychomotor speed although other domains may be involved.
Perivascular spaces, particularly enlarged perivascular spaces, detected on MRI, are part of SVD and have been theorized to be contributors to cognitive decline. However, this was not supported in a study by Benjamin et al
who reported that lacunar infarcts were predictors of cognitive decline but not perivascular spaces. This finding was supported by a meta-analysis of five population-based studies of enlarged perivascular spaces and cognition
and are another biomarker of cerebral SVD. They are best detected by MRI techniques which are sensitive to iron deposits such as gradient-echo T2*-weighted and susceptibility-weighted imaging.
CMBs are seen in 68% of spontaneous ICH patients and 40% of those with ischemic stroke and their prevalence tends to mirror other components of SVD in ischemic stroke.
Although often seen together in neuropathological studies of dementia, CMBs and cerebral microinfarctions are associated with different microvascular alterations.
CAA was determined to be important in the cognitive decline associated with AD which once again reflects the overlap between neurodegenerative disease and vasculopathy.
White matter degeneration
There is an evolving perception of what has been termed “white matter degeneration” playing a key role in cognitive impairment both in the vascular and neurodegenerative realm.
There are various designations for the prominent white matter findings typically seen on MRI in cerebral SVD (Table 4). Substrates of this white matter degeneration include: myelin loss, axonal dysfunction, arteriolosclerosis with resultant lacunar infarcts,
It is also, not unexpectedly, associated with small artery occlusion-type stroke as opposed large artery atherosclerotic or major cardioembolic stroke.
and this presumably reflects the vascular/degenerative contribution of white matter disease to the spectrum of dementia including AD and VaD. White matter disease burden can be stratified according to MRI markers of vascular injury to develop a risk profile for ischemic stroke, ICH and dementia.
A term that has developed to try to tie together various components of the pathogenesis in white matter disease related to ischemia is “ischemic demyelination”.
propose various contributing factors which may include chronic deep borderzone territory hypoperfusion, small vessel mechanical injury related to increased pulsatile motion with resultant tortuosity of deep white matter arterioles, associated with aging and hypertension, as well as periventricular venous collagenosis with secondary stenosis. Dysfunction of the blood-brain barrier (BBB) related to ageing and microvascular disease has also been implicated.
in a MRI based study of WMH, reported a link between BBB impairment and cerebral hypoperfusion with cerebral SVD and noted that a similar link has been found in AD. In addition, proposed disruption of glial cells, important for axonal support, may play a pivotal role.
Although less emphasized, presumably related to the lower incidence compared to ischemic stroke, hemorrhagic stroke is often associated with cognitive impairment. The neuropsychological sequelae are reported to be less well established for hemorrhagic stroke with several domains identified in terms of possible presentation.
looked at the long-term risk of dementia after ischemic and hemorrhagic stroke. They reported a 30-year absolute risk of dementia of 11.5%. The hazard ratio for dementia after any type of stroke was 1.80 and was 1.72 after ischemic stroke, 2.70 after ICH and 2.74 after subarachnoid haemorrhage (SAH). Thus, there was a particularly high risk with hemorrhagic stroke and they observed that younger patients were at higher risk for post-stroke dementia than older patients and this was not impacted by gender or pre-existing vascular conditions. In a hospital-based study of ICH,
all patients had cognitive impairment with episodic memory loss most frequent followed by psychomotor speed, executive function and then language and visuoconstructive abilities. Dementia was observed in 23% and was related to ICH volume as well as functional score on discharge. In a prospective study of spontaneous ICH with resultant dementia,
the incident rate was 14.2% within one year of the ictus and rose to 28.3% at four years. The risk of dementia was associated with lobar hematoma, presence of superficial hemosiderosis, cortical atrophy score, higher number of CMBs and older age. Biffi et al
looked at risk factors associated with early versus later onset dementia following ICH with six months as the cut-off. Early dementia was associated with hematoma size and lobar location while educational level, mood disorder and white matter disease on CT brain scan was associated with later onset dementia. It was pointed out, in an accompanying editorial,
It is reported that “mixed” CMBs, i.e. deeper and lobar locations, as well as higher load correlates with cognitive decline and dementia with hypertensive vasculopathy and CAA as presumptive contributors.
of 434 participants without dementia, beta-amyloid and tau positron emission tomography (PET) scanning was used to look at potential correlation with WMH and CMBs seen on MRI. The amyloid burden correlated with both, with CAA invoked as a suggested contributor to this relationship, but this was not seen with tau burden. However, CAA was not reported to be an important contributor to cortical microinfarcts in a study of Kovari et al.
As previously mentioned, aneurysmal SAH is commonly associated with ongoing cognitive deficit even when there is otherwise good functional outcome. This could be related the diffuse pathophysiological alterations that can be seen in association with aneurysmal rupture such as diffuse cerebral edema, obstructive hydrocephalus, vasospastic-mediated infarcts and hematoma formation. As mentioned above, the hazard ratio of 2.74 for dementia associated with SAH was the highest for any stroke type. Geraghty et al
reinforced this message with their study in which 288 SAH patients were compared to 80 control patients. Of the 105 SAH patients available for MoCA exam, 56.2% had scores < 22 compared to 28.7% of controls. Despite this clinically significant cognitive impairment, the functional outcome at discharge was reportedly good, overall, with a mean modified Rankin scale of 1.8. This adverse effect on cognition following SAH may be related to diffuse pial microvasospasms based upon a mouse model study in which nitric oxide inhalation was associated with significantly improved outcome.
Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.
reported that early ambulation following aneurysmal SAH was associated with improved functional outcome including protection against dementia.
Genetic factors involved in VaD
There are increasingly recognized genetic factors playing a role in stroke predisposition which includes well recognized risk factors for stroke that tend to run in families such as hypertension, diabetes mellitus, hyperlipidemia and coronary artery disease. Pendlebury and Rothwell
performed a systematic review and meta-analysis of factors associated with both pre-stroke and post-stroke dementia. Factors significantly associated with pre-stroke dementia, with odds ratio (OR), included: female sex (2.3), low education (2.1), positive family history of stroke (4.5), diabetes mellitus (1.5), atrial fibrillation (1.9), ischemic heart disease (1.8), previous transient ischemic attack (1.8) and hypertension (1.4). Factors significantly associated with post-stroke dementia, with OR, included: female sex (1.3), low education (2.5), diabetes mellitus (1.4), atrial fibrillation (2.0), prior stroke (1.9) and multiple strokes (2.5). Somewhat surprisingly, hypertension was reported to only be a significant factor for pre-stroke dementia while smoking was reported as a protective factor in pre-stroke dementia (0.5).
Genetic forms of stroke associated with dementia include CADASIL, CARASIL, which is an autosomal recessive form of CADASIL, cerebral retinal vasculopathies, retinal vasculopathy with with cerebral leukoencephalopathy and systemic manifestations (RVCLSM), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) and COL4A1 mutations with combined small vessel and large arterial disease.
CADASIL is one of the more common genetic-mediated examples of SVD and is associated with a NOTCH3 on chromosome 19 mutation and characterized by migraine, recurrent small vessel infarcts and progressive dementia. The MRI brain scan findings include WMH, lacunes, CMBs and brain atrophy (Fig. 3). The presence of WMH and dilated perivascular spaces in anterior temporal poles, subinsular areas and superior frontal gyri is viewed as characteristic of CADASIL.
Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison.
Fig. 3(a) Computed tomography (CT) brain scan showing bilateral centrum semiovale hypodensity in patient with vascular dementia correlated with (b) FLAIR MRI sequence shows prominent hyperintensity indicative of leukoaraiosis. Gradient echo (MR) images demonstrating cerebral microbleeds of c. the brainstem and cerebellum as well as multiple subcortical locations (d and e).
CARASIL is an autosomal recessive disorder, caused by a mutation in HtrA serine protease (HTRA1) gene. The associated microangiopathy presents as a leukoencephalopathy with the appearance of multi-focal infarcts.
Hereditary endotheliopathy with retinopathy, neuropathy and stroke (HERNS) is associated with multiple cerebral infarcts, similar to those seen in CADASIL, and is linked to a single locus on chromosome 3p21.1-p21.3.
Other genetically mediated cerebral small vessel disease disorders, which can be associated with dementia, include: collagen type IV mutations, forkhead box C1 mutations and hereditary cerebral amyloid CAA.
The mitochondrial disorder termed mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) can result in cognitive impairment as can Fabry disease, a rare x-linked genetic disorder associated with alpha galactosidase A enzyme deficiency, which can result in painful neuropathy and recurrent stroke.
Neuroimaging in vascular dementia
The diagnosis of dementia, in general, is predicated on the results of neuroimaging in recognition that various abnormalities, such as meningioma, communicating hydrocephalus and chronic subdural hematoma, can present with progressive cognitive decline but can be potentially very responsive to intervention. On CT brain scan, macroinfarction, extensive white hypoluncency and associated atrophy can be identified in support of a vascular ischemic etiology for the dementia (Fig. 3 a). Both generalized and hippocampal atrophy can be associated with VaD. MRI brain scan is generally more informative in the evaluation of dementia and is considered the “gold standard” for evaluation on a neuroimaging basis (Fig. 3 b).
CMBs can also be detected on gradient echo (GRE) MRI brain scan (Fig. 3 c-e). The fluid attenuation inversion recovery (FLAIR) MRI is particularly helpful in the assessment of WMH and lacunes (Fig. 4), The location and extent of WMH on MRI are important in post-stroke cognitive performance as supported by the TABASCO Study
Only white matter hyperintensities predicts Post-stroke cognitive performance among cerebral small vessel disease markers: Results from the TABASCO Study.
A 7 tesla (7T) MRI brain scan may be needed for the detection of microinfarction and to help better characterize hereditary vascular causes of dementia such as CADASIL, Fig. 5.
In a post-mortem 7T MRI of neurodegenerative dementia and VaD, deep white matter lacunar infarcts in VaD helped to distinguish it from neurodegenerative dementia.
Topographic distribution of white matter changes and lacunar infarcts in neurodegenerative and vascular dementia syndromes: A post-mortem 7.0 tesla magnetic resonance imaging study.
Fig. 5Fluid attenuation inversion recovery (FLAIR) MRI brain scan in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is a diffuse subcortical hyperintensity pattern which is associated with migraine headache, cognitive impairment and recurrent stroke.
As mentioned previously, white matter disease can have considerable overlap in terms of mechanism with the term “ischemic demyelination” not uncommonly used in MRI brain scan reports. One particular clinical challenge can be the distinction of SVD from a demyelinating disorder such as primary progressive multiple sclerosis. Of potential value in this regard, Samaraweera et al
demonstrated that white matter lesion central veins, seen on 3T MRI, using a T2*-weighted sequence, could be used in support of multiple sclerosis over SVD when present.
Newer MRI techniques can assess for cerebral perfusion, cerebrovascular reactivity, BBB permeability as well as white matter microarchitecture.
Diffusion tensor imaging (DTI) is particularly valuable for white matter integrity including connectivity. In a DTI study of microstructural alterations of the hippocampus in VaD,
damage to the connectivity was observed despite normal appearing gray matter on conventional MRI. Fig. 6 demonstrates potential changes, reflective of VaD, detected by DTI MRI. One particular potential value of DTI and other MRI modalities in VCI and VAD is to monitor the course of the structural alterations over time which might provide not only prognostic information but might also provide objective assessment the response to intervention.
Fig. 6Diffusion tensor image (DTI) derived maps with fractional anisotropy (FA), a measure of the integrity of white matter tracts. There is reduced FA in the area of ischemic demyelination (green) compared to normal white matter (orange). Parallel diffusivity, which represents axonal damage, is increased in the abnormal myelin. Perpendicular diffusivity is also increased in the abnormal myelin and reflects myelin integrity with increased diffusivity reflective of abnormal myelinisation. Such imaging has the potential to allow quantitative monitoring of subclinical or subtle progression of cerebral small vessel disease over time as well as potential response to intervention.
Cerebral PET is reported to be of value in distinguishing characteristic patterns of neurodegenerative dementia, on PET, from the patchy involvement supportive of VaD.
There are standard blood tests for cognitive impairment such as thyroid function, metabolic profile, vitamin B12 and folate levels as well as screening for connective tissue disorders, neurosyphilis, HIV-related disease, neuroborreliosis and neurosarcoidosis when appropriate. Cerebrospinal fluid exam can help support AD as can cerebral PET scan. Genetic testing is increasingly available for certain uncommon disorders associated with SVD, but tends to be relatively expensive and should be reserved for clinical suspicion of higher yield entities such as CADASIL.
Prevention and treatment
VaD and VCI are, theoretically, very preventable disorders in most instances. Certainly, however, genetic factors can supersede a healthy lifestyle. Promotion of optimal control of hypertension and diabetes mellitus, when present, is viewed to be of established value.
The actual prevention of dementia with effective blood pressure control appears to be affected by the degree of control and the age of onset that such control is achieved as well as the adaptation to the duration and degree of hypertension through what has been termed cerebral vessel remodeling.
The SPRINT MIND Investigators for the SPRINT Research Group Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial.
reported reduction in the risk of MCI in intensive versus standard blood pressure control by 20% with a 16% risk reduction both MCI and probable dementia. However, no statistically significant reduction was seen for probable dementia alone with a systolic blood pressure target of < 120 mmHg versus < 140 mg. In a substudy analysis,
Effects of intensive versus standard blood pressure control on domain-specific cognitive function.: a substudy of the SPRINT randomised controlled trial.
Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study.
reported, in a pathology study, that poorly controlled blood pressure from early adulthood into midlife, was associated with increased WMH volume and smaller brain volumes at ages 69 to 71. In a study of type 2 diabetes mellitus and cerebral SVD,
an association was found particularly for lacunar stroke and fractional anisotropy (FA), on DTI MRI, but not on WMH volume. Factors related to atherosclerosis in midlife, in general, are associated with VaD and cerebral SVD, but this relationship was not found for AD according to Gustavsson et al.
with the association greatest for involvement of the anterior cerebral artery, but this was not found for the middle cerebral artery. Well established risk factors for stroke, such as AF, are now increasingly more manageable and perhaps help to explain the overall reduction in prevalence of VaD over time according to the Framingham study.
Cholinesterase inhibitor agents are used rather commonly for AD, especially in earlier stages of this disease. They are also not uncommonly used in VaD, but with less evidence to support their use. They might be of particular value when the dementia is suspected to be of the mixed AD/VaD type. One meta-analysis suggested that they provide protection against further decline
Kim JO, Lee SJ, Pyo J-S.Effect of acetylcholine inhibitors on post-stroke cognitive impairment and vascular dementia. A meta-analysis. PLoS One202; 15:e00227820, PMID 32032361.
Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia.
These agents are generally well tolerated but have the potential for significant gastrointestinal side effects and can promote clinically significant bradycardia. Memantine, an N-methyl D-aspartate (NMDA) receptor antagonist, is also used despite limited,
documentation of its efficacy. From a practical standpoint, assessment of possible clinical response to either a cholinesterase inhibitor and/or memantine appears to be an approach to be considered based upon presently available information.
Summary
There is a clear overlap between vascular and neurodegenerative contributions to cognitive decline as part of the aging process. Effective strategies for prevention and intervention of large vessel stroke has placed further emphasis on cerebral small vessel disease in combination with neurodegenerative mechanisms. Elegant research, to date, has not translated into effective interventional strategies once VCI, VaD or VaD in combination with AD, leaves the patient with progressive loss of functional independence and quality of life. This review underscores that, as life expectancy increases, related to impressive advances in cardiovascular and cancer therapies, VaD, especially that related to SVD, will be of increasing concern.
Declarations of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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