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Emerging Concepts in Vascular Dementia: A Review

      Highlights

      • Vascular mechanisms are increasingly recognized as a contributing factor to dementia in the elderly
      • Vascular dementia generally reflects a heterogeneity in terms of presentation related to the varying distributions of vascular involvement
      • Small vessel ischemic disease overlaps with both vascular and neurodegenerative dementia and has become an increasing focus of study
      • Hemorrhagic stroke is often associated with clinically significant cognitive deficit although its contribution to the spectrum of vascular dementia tends to be less emphasized
      • 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.

      Key Words

      Introduction

      Vascular dementia (VaD)
      • Grinberg LT
      • Heinsen H.
      Toward a pathological definition of vascular dementia.
      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.
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      Mixed dementia—the most common cause of dementia.
      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”.
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      ,
      American Psychiatric Association
      Fig 1
      Fig. 1Potential pathogenic pathways for vascular dementia. HTN = hypertension, DM = diabetes mellitus, HLD = hyperlipidemia.

      Diagnostic criteria for vascular dementia

      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.
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      Observations on the brains of demented old people.
      The heterogeneous nature of VaD has led to different criteria being proposed.
      • Wetterling T
      • Kanitz RD
      • Borgis KJ.
      Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN).
      Scheltens and Hijdra
      • Scheltens P
      • Hijdra AH.
      Diagnostic criteria for vascular 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,
      • Hachinski V
      • Iadecola CC
      • Petersen RC
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      National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.
      the ADDTC
      • Roman GC
      • Tatemichi TK
      • Erkinjuntti T
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      Vascular dementia: diagnostic criteria for research studies.
      and the NINDS-AIREN.
      • Chui HC
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      • Shankle R
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      Criteria for the diagnosis of ischemic vascular dementia proposed by the state of California Alzheimer's disease diagnostic and treatment centers.
      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.
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      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,
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      Clinical diagnosis of 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”.
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      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      To reflect greater inclusiveness of the various mechanisms, including hemorrhagic stroke, the term Vascular Cognitive Impairment (VCI) has been proposed
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      Vascular cognitive impairment.
      as has Post-Stroke Dementia (PSD).
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      Poststroke dementia.
      Table 1. Terminology of vascular dementia.
      TerminologyDescription/cause
      Small vessels disease (SVD) /Binswanger's diseaseSub-cortical infarcts (HTN/DM)
      Multi-infarct dementiaCortical infarct, large artery occlusion (atherothrombotic or cardioembolic)
      StrategicThalamus, caudate, hippocampus and genu of internal capsule
      Hypoperfusion dementiaWater shed infarct/ orthostatic hypotension and variation in blood pressure
      Mixed dementiaVascular disease along with Alzheimer disease or Dementia of leiw body
      HemorrhagicMicro-bleed, CAA (APP codon 693 mutation)
      Hereditary vascular dementiaCADASIL (NOTCH 3 gene mutation) and CARASIL (mutation in HtrA serine protease gene)
      Vascular dementia/Vascular cognitive impairment/post-stroke dementiaAll of the above causes
      This evolving terminology of VaD was emphasized by a 2106 International Congress on Vascular Dementia
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      Is the time ripe for new diagnostic criteria of cognitive impairment due to cerebrovascular disease?.
      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
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      • Duering M
      • Hachinski V
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      Vascular cognitive impairment and dementia.
      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.
      • Robinson RG
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      Post-stroke depression: a review.
      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
      • Liu F
      • Tsang RC
      • Zhou J
      • Zhou M
      • Zha F
      • Long J
      • Wang Y.
      Relationship of Barthel index and its short form with the modified rankin scale in acute stroke patients.
      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.
      NumberCriteria
      1Clinical presentation of stroke 3 to 6 months of onset
      2Neuro-imaging support of either macro-, lacunar or micro-infarction
      3Characteristics of cognitive deficit supportive of vascular etiology
      4Manifestations of stroke residua on exam
      5Risk factors of stroke
      6Clinical course compatible with maximal deficit at ictus followed by improvement
      7Familial factors supportive of stroke

      Epidemiology

      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.
      • Llibre Rodriguez JJ
      • Ferri CP
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      Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey.
      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
      • Pendlebury ST
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      • de Jager
      • Zamboni G
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      • Rothwell PM.
      Differences in cognitive profile between TIA, stroke and elderly memory research subjects: a comparison of MMSE and MoCA.
      and is particularly reliable, in this regard, according to Freitas et al.
      • Freitas S
      • Simoes MR
      • Alves L
      • Vincente M
      • Santana I.
      Montreal cognitive assessment (MoCA): validation study for vascular dementia.
      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.
      • Chui HC
      • Mack W
      • Jackson JE
      • et al.
      Clinical criteria for the diagnosis of vascular dementia—a multicenter study of comparability and interrater reliability.
      • Knopman DS
      • Parisi JE
      • Boeve BF
      • et al.
      Vascular dementia in a population-based autopsy study.
      • Gold G
      • Giannakopoulos P
      • Montes-Paixao Junior C
      • et al.
      Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia.
      • Wolters FJ
      • Ikram A.
      Epidemiology of vascular dementia.
      Based on a Canadian Study of Health,
      • He´bert R
      • Lindsay J
      • Verreault R
      • Rockwood K
      • Hill G
      • Dubois MF.
      Vascular dementia: incidence and risk factors in the Canadian study of health and aging.
      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
      • Wolters FJ
      • Ikram A.
      Epidemiology of vascular dementia.
      ,
      • Lobo A
      • Launer LJ
      • Fratiglioni L
      • et al.
      Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the elderly research group.
      with the percentage closer to 30% in Asia and developing countries.
      • Kalaria RN
      • Maestre GE
      • Arizaga R
      • et al.
      Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors.
      The global frequency of autopsy-verified VaD has been estimated to be around between 10-15%, but with considerable variation reported.
      • Zhang Y
      • Xu Y
      • Nie H
      • et al.
      Prevalence of dementia and major dementia subtypes in the Chinese populations: a meta-analysis of dementia prevalence surveys, 1980-2010.
      • Catindig JA
      • Venketasubramanian N
      • Ikram MK
      • Chen C.
      Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk factors.
      • Fratiglioni L
      • Launer LJ
      • Andersen K
      • et al.
      Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group.
      • Ikeda M
      • Hokoishi K
      • Maki N
      • et al.
      Increased prevalence of vascular dementia in Japan: a community-based epidemiological study.
      Men tend to be affected more frequently than women
      • Leys D
      • Henon H
      • Mackowiak-Cordoliani MA
      • Pasquier F.
      Poststroke dementia.
      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.
      • Gorelick PB
      • Scuteri A
      • Black SE
      • et al.
      Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American heart association/american stroke association.
      In the Framingham Heart Study,
      • Satizabal CL
      • Beiser AS
      • Chouraki V
      • Chene G
      • Dufoull C
      • Seshadri S.
      Incidence of dementia over three decades of the Framingham Heart Study.
      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.
      • Hachinski V
      • Iadecola CC
      • Petersen RC
      • et al.
      National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.
      ,
      • Ballard C
      • O'Sullivan MJ
      Alzheimer disease and stroke: cognitive and neuroimaging predictors of AD and stroke.
      Both VaD and AD are associated with medial temporal lobe and hippocampal atrophy as well as variable degrees of hippocampal sclerosis.
      • Kalaria RJ.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      Brun and Englund
      • Brun A
      • Englund E.
      A white matter disorder in the dementia of the Alzheimer type: a pathoanatomical study.
      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.
      • Lee S
      • Viqar F
      • Zimmerman ME
      • et al.
      White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer Network.
      • Beeri MS
      • Ravona-Springer R
      • Silverman JM
      • Haroutunian V.
      The effects of cardiovascular risk factors on cognitive compromise.
      • Mielke MM
      • Rosenberg PB
      • Tschanz J
      • et al.
      Vascular factors predict rate of progression in Alzheimer disease.

      Clinical characteristics

      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.
      • Korczyn AD
      • Vakhapova V
      • Grinberg LT.
      Vascular dementia.
      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.
      • O'Brien JT
      • Thomas A.
      Vascular dementia.
      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.
      • Ylikoski R
      • Jokinen H
      • Andersen P
      • et al.
      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.
      • Gupta M
      • Dasgupta A
      • Khwaja GA
      • Chowdhury D
      • Patidar Y
      • Batra A.
      Behavioral and psychological symptoms in poststroke vascular cognitive impairment.
      In a study of neuropsychiatric symptoms in VaD, using a 12-item Neuropsychiatric Inventory, Santos et al
      • Santos MAO
      • Bezerra LS
      • CdC Correia
      • Bruscky IS.
      Neuropsychiatric symptoms in vascular dementia. Epidemiologic and clinical aspects.
      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.
      • Kalaria RJ.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      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
      • Korczyn AD
      • Vakhapova V
      • Grinberg LT.
      Vascular dementia.
      ,
      • Iadecola C.
      The pathobiology of vascular dementia.
      ,
      • Vinters HV
      • Zarow C
      • Borys E
      • et al.
      Review: Vascular dementia: clinicopathologic and genetic considerations.
      as well as remote effects including what has been termed diaschisis.
      • Carrer E.
      • Tononi G.
      Diaschisis: past, present, future.
      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
      • Geovanini G-R
      • Libby P.
      Atherosclerosis and inflammation: overview and Updates.
      as well as to cerebral SVD.
      • Low A
      • Mak E
      • rowe JB
      • Markus HS
      • O'Brien J
      Inflammatin and cerebral small vessel disease.
      Due to this heterogeneity of pathophysiologic mechanism, a consensus on defined pathogenesis has not been established.
      • Iadecola C.
      The pathobiology of vascular dementia.
      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.
      • Korczyn AD
      • Vakhapova V
      • Grinberg LT.
      Vascular dementia.
      ,
      • Iadecola C.
      The pathobiology of vascular dementia.
      ,
      • Vinters HV
      • Zarow C
      • Borys E
      • et al.
      Review: Vascular dementia: clinicopathologic and genetic considerations.
      Fig 2
      Fig. 2Potential cellular and molecular mechanism of vascular dementia. HIFαAB = hypoxic inducible factor alpha/beta, eNOS = endothelial nitric oxide synthase, iNOS = inducible isoform nitric oxide synthase, P75NTR = p75 neurotropin factor, ROS = reactive oxygen species, IL-6= interleukin 6, TNF-α = tumor necrosis factor-α, BDNF = brain-derived neurotrophic factor

      Cerebral Macroinfarction:

      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.
      • Kalaria RJ.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      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.
      • Hart RG
      • Catanese L
      • Perera KS
      • Ntaios G
      • Connolly SJ.
      Embolic stroke of undetermined source.
      Macro-infarction is typically more than 10 mm in greatest dimension. According to the NINDs-AIREN criteria,
      • Roman GC
      • Tatemichi TK
      • Erkinjuntti T
      • et al.
      Vascular dementia: diagnostic criteria for research studies.
      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.
      • Kalaria RJ.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      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.
      • Iadecola C
      • Duering M
      • Hachinski V
      • et al.
      Vascular cognitive impairment and 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.
      • Kalaria RJ.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      The hallmarks of SVD on MRI brain scan are: (1) white matter hyperintensities (WMH), (2) lacunar infarcts and (3) cerebral microbleeds (CMBs).
      • Jimez-Balado J
      • Llena I
      • Abril O
      • et al.
      Cognitive impact of cerebral small vessel disease changes in patients with hypertension.
      There is a correlation between WMH and progressive cognitive decline.
      • Prins ND
      • van Dijk EJ
      • den Hiejer T
      • et al.
      Cerebral small vessel disease and decline in information processing speed, executive function and memory.
      • van den Heuvel DM
      • ten Dam VH
      • de Craen AJ
      • et al.
      Increase in periventricular hyperintensities parallels decline in mental processing speed in non-demented elderly population.
      • Ulterwijk R
      • Staals J
      • Huijts M
      • de Leeuw PW
      • Kroon AA
      • van Oostenbrugge RJ.
      MRI progression of cerebral small vessel disease and cognitive decline in patients with hypertension.
      This is not only reflective of a vascular component to the cognitive impairment as WMH is also a marker of neurodegenerative pathology such as AD.
      • van den Berg E
      • Geerlings M
      • Jan Biessels G
      • Nederkorn PJ
      • Kloppenberg RP
      White matter hyperintensities and cognition in mild cognitive impairment and Alzheimer's disease: A domain-specific meta-analysis.
      SVD, including micro-infarcts and lacunar infarcts, is an important contributor to pure vascular dementia based upon neuropathological studies.
      • Esiri MM
      • Wilcock GK
      • Morris JH.
      Neuropathological assessment of the lesions of significance in vascular dementia.
      ,
      • Strozyk D
      • Dickson DW
      • Lipton RB
      • et al.
      Contribution of vascular pathology to the clinical expression of dementia.
      In an aging study, micro-infarction and lacunar infarction was viewed as the primary contributor to 34% of all definitive dementia.
      • White L
      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.
      Similar findings were reported in greater than 50% of elderly subjects with VaD in another study
      • Smallwood A
      • Oulhaj A
      • Joachim C
      • et al.
      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.
      with further support provided in the Geneva brain aging study.
      • Giannakopoulos P
      • Gold G
      • Kovari E
      • et al.
      Assessing the cognitive impact of Alzheimers disease pathology and vascular burden in the aging brain.
      Table 3Cerebral small vessel disease components.
      NumberComponents
      1Cerebral microinfarctions
      2Lacunar infarct
      3White matter hyperintensities
      4Cerebral microbleeds
      5Cortical superficial siderosis
      6MRI visible vascular spaces
      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.
      • Attems J
      • Jelliinger KA.
      The overlap between vascular disease and Alzheimer's disease – lessons from pathology.
      Nolan et al,
      • Nolan KA
      • Lino MM
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      • Blass JP.
      Absence of vascular dementia in an autopsy series from a dementia clinic.
      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”.
      • Smith E
      • Schneider JA
      • Wardlaw JM
      • Greenberg SM.
      Cerebral microinfarcts: the 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
      • Arvanitakis Z
      • Leurgans SE
      • Barnes LL
      • Bennet DA
      • Schneider JA.
      Microinfarct pathology, dementia and cognitive systems.
      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.
      • Yoshita M
      • Fletcher E
      • DeCarli C.
      Current concepts of analysis of cerebral white matter hyperintensities on magnetic resonance imaging.
      Such techniques can provide reliable quantitative measures of WMH burden over time.
      • Wang R
      • Li C
      • Wang J
      • et al.
      Automatic segmentation and quantitative analysis of white matter hyperintensities on FLAIR images using trimmed-likelihood estimator.
      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.

      Fazekas F, Kleinert R, Offenbacher H, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology1993;43:1683-1689.

      There are potential temporal dynamics, however, in the imaging process. For example, der Tilgte et al
      • ter Telgte A
      • Wiegertjes K
      • Gesierich B
      • et al.
      Temporal dynamics of cortical microinfarcts in cerebral small vessel disease.
      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.
      • Gurol ME
      • Biessels GJ
      • Polimeni JR.
      Advanced neuroimaging to unravel mechanisms of cerebral small vessel diseases.
      Many of the imaging studies have placed emphasis on hypertension seen in roughly two-thirds of patients beyond age 60 in the United states,
      • Fryar CD
      • Ostchega Y
      • Hales CM
      • Zhang G
      • Kruszon-Moran D.
      Hypertension prevalence and control among adults: United States 2015-2016.
      and the most common risk factor for SVD.
      • Deramecourt V
      • Slade JY
      • Oakley AE
      • et al.
      Staging a natural history of cerebrovascular pathology in dementia.
      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.
      • Scharf EL
      • Graff-Radford J
      • Przybelski SA
      • et al.
      Cardiometabolic health and longitudinal progression of white matter hyperintensity. The Mayo Clinic Study of Aging.
      In a pathological evaluation of dementia, through a longitudinal, population-based study,
      • Brundel M
      • de Bresser J
      • van Dillen JJ
      • Kappelle LJ
      • Biessels GJ.
      Cerebral microinfarcts: a systematic review of neuropathological studies.
      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.
      • Sonnen JA
      • Larson EB
      • Crane PK
      • et al.
      Pathological correlates of dementia in a longitudinal, population-based sampling of aging.
      The correlation between WMH and hypertension might not only reflect persistent suboptimal blood pressure control but also blood pressure variability.
      • Ma Y
      • Song A
      • Viswanathan A
      • et al.
      Blood pressure variability and cerebral small vessel disease. A systematic review and meta-analysis of population-based cohorts.
      A number of studies have determined correlation between MRI assessment of certain features of SVD and cognitive decline.
      • Lawrence AJ
      • Zeestraten EA
      • Benjamin P
      • et al.
      Longitudinal decline in structural networks predicts dementia in cerebral small vessel disease.
      • Zeestraten EA
      • Lawrence AJ
      • Lambert C
      • et al.
      Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease.
      • Tozier DJ
      • Zeestraten E
      • Lawrence AJ
      • Barrick TR
      • Markus HS.
      Texture analysis of T1-weighted and fluid attenuation inversion recovery images detects abnormalities that correlated with cognitive decline in small vessel disease.
      • Smith EE
      • Beaudin EE.
      New insights into cerebral small vessel disease and vascular cognitive impairment from MRI.
      As an example of the clinical utility of such an assessment, Al Olama et al
      • Al Olama AA
      • Wason JMS
      • Tuladhar AM
      • et al.
      Simple MRI score aides prediction of dementia in cerebral 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
      • Yilmaz P
      • Ikram MK
      • Niessen WJ
      • Ikram MA
      • Vernooij MW.
      Practical small vessel disease score relates to stroke, dementia, and death.

      Cerebral Microinfarction

      In a systematic review of cerebral microinfarction (CMI),
      • Brundel M
      • de Bresser J
      • van Dillen JJ
      • Kappelle LJ
      • Biessels GJ.
      Cerebral microinfarcts: a systematic review of neuropathological studies.
      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.
      • Sonnen JA
      • Larson EB
      • Crane PK
      • et al.
      Pathological correlates of dementia in a longitudinal, population-based sampling of aging.
      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.
      • van Veluw SJ
      • Shih AY
      • Smith EE
      • et al.
      Detection, risk factors, and functional consequences of cerebral micoinfarcts.
      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.
      • van Veluw SJ
      • Jouvent E.
      • Charidimou A.
      Editorial: cerebral small vessel diseases: from vessel alterations to cortical parenchymal injury.

      Lacunar Infarction

      The concept of lacunar infarction was popularized by C. Miller Fisher based upon elegant neuropathological investigation.
      • Fisher CM.
      The arterial lesions underlying lacunes.
      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.
      • Pasi M
      • Cordonnier C.
      Clinical relevance of cerebral small vessel diseases.
      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.
      • Wardlaw JM
      • Smith EE
      • Biessel GJ
      • et al.
      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.
      • Caplan LR.
      Lacunar infarction and small vessel disease pathology and pathophysiology.
      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”.
      • Tomimoto H.
      Subcortical vascular dementia.
      Makin et al
      • Makin SDJ
      • Turpin S
      • Dennis MS
      • Wardlaw JM.
      Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence, and comparison with other stroke subtypes.
      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.
      • Fisher CM.
      The arterial lesions underlying lacunes.
      ,
      • Edwards JD
      • Jacova C
      • Sepehry AA
      • Pratt B
      • Benavente OR.
      A quantitative systematic review of domain-specific cognitive impairment in lacunar stroke.
      Gray matter lacunar infarcts are reported to be independent predictors of cognitive decline in the elderly.
      • Gold G
      • Kovari E
      • Herrmann FR
      • et al.
      Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia.
      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
      • Benjamin P
      • Trippier S
      • Lawrence AJ
      • et al.
      Lacunar infarcts but not perivascular spaces are predictors of cognitive decline in cerebral small-vessel disease.
      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
      • Hilal S
      • Tan CS
      • Adams HHH
      • et al.
      Enlarged perivascular spaces and cognition: a meta-analysis of 5 population-based studies.

      Cerebral microbleeds (CMB) and cerebral amyloid angiopathy

      CMBs are small foci of acute, subacute or chronic blood products
      • Wu Y
      • Chen T.
      An Up-to-Date review on cerebral microbleeds.
      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.
      • Renard D
      Cerebral microbleeds: a magnetic imaging review of common and less common causes.
      Cerebral SVD hypertensive vasculopathy and cerebral amyloid angiopathy (CAA) are the most frequent pathologies associated with CMBs.
      • Gurol ME
      • Greenberg SM.
      Cerebral amyloid angiopathies.
      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.
      • Koennecke H-C.
      Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications.
      CAA is associated with amyloid-ß peptides within the walls of leptomeningeal and cortical vessels
      • Wu Y
      • Chen T.
      An Up-to-Date review on cerebral microbleeds.
      can be either sporadic or genetically mediated and is associated with ICH and cognitive impairment.
      • Charidimou A
      • Boulouis G
      • Gurol ME
      • et al.
      Emerging concepts in sporadic amyloid angiopathy.
      Although often seen together in neuropathological studies of dementia, CMBs and cerebral microinfarctions are associated with different microvascular alterations.
      • van Veluw SJ
      • Scherlek AA
      • Freeze WM
      • et al.
      Different microvascular alterations underlie microbleeds and microinfarcts.
      A high number of CMBs are associated with an increased risk of cognitive deficit including dementia.
      • Akoudad S
      • Wolters FJ
      • Viswanathan A
      • et al.
      Association of cerebral microbleeds with cognitive decline and dementia.
      The coexistent findings of CMBs, as well as actual CAA, is felt to contribute to the spectrum of cognitive impairment on a vascular basis
      • Vinters HV
      • Zarow C
      • Borys E
      • et al.
      Review: Vascular dementia: clinicopathologic and genetic considerations.
      ,
      • Wu Y
      • Chen T.
      An Up-to-Date review on cerebral microbleeds.
      with potential contribution of BBB leakage.
      • Freeze WM
      • Bacskai BJ
      • Frosch MP
      • et al.
      Blood-brain barrier leakage and microvascular lesions in cerebral amyloid amyloid angiopathy.
      In a community-based study of the elderly,
      • Boyle PA
      • Yu L
      • Nag S
      • et al.
      Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons.
      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.

      Roseborough A, Hachinski V, Whitehead. White matter degeneration-A treatable target?JAMA Neurology202077:793-794.

      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,
      • Roman GC.
      On the history of lacunes, etat crible’ and the white matter lesions of vascular dementia.
      microinfarcts, microbleeds and perivascular spacing.
      • Hase Y
      • Horsburgh K
      • Ihara M
      • Kalaria RN.
      White matter degeneration in vascular and other ageing-related dementias.
      Of interest, periventricular hyperintensities are reported to be associated with elevated cerebral amyloid independent of vascular risk factors.
      • Marnane M
      • Al-Jawadi OO
      • Mortazavi S
      • et al.
      Periventricular hyperintensities are associated with elevated cerebral amyloid.
      WMH, whatever the pathogenic mechanism, are associated with impairment in executive function and a two-fold increased dementia risk.
      • Debette S
      • Markus HS.
      The clinical importance of white matter hyperintensities on brain magnetic resonance imaging; systemic review and meta-analysis.
      It is also, not unexpectedly, associated with small artery occlusion-type stroke as opposed large artery atherosclerotic or major cardioembolic stroke.
      • Giese A-K
      • Schirmer MD
      • Dalca AV
      • et al.
      White matter hyperintensity burden in acute stroke patients differs by ischemic stroke subtype.
      In addition, it is reported that the extent of WMH correlates with the risk of recurrent stroke in patients with first ever ischemic stroke.
      • Fu JH
      • Lu CZ
      • Hong Z
      • Dong Q
      • Luo Y
      • Wong KS.
      Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischemic stroke.
      There is an association between WMH and aging with moderate to severe global cerebral atrophy, including hippocampal atrophy,
      • Al-Janabi OM
      • Panuganti P
      • Abner EL
      • et al.
      Global cerebral atrophy detected by routine imaging: relationship with age, hippocampal atrophy, and white matter disease.
      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.
      • Debette S
      • Schilling S
      • Duperron M-G
      • Larsson SC
      • Markus HS.
      Clinical significance of magnetic resonance imaging markers of vascular brain injury: A systematic review.
      This may correlate with the white matter atrophy which is also reportedly seen in association with CAA.
      • Fotladis P
      • Reijmar YD
      • van Veluw SJ
      • et al.
      White matter atrophy in cerebral amyloid angiography.
      Table 4Ischemic white matter disease designations.
      NumberDesignations
      1White matter disease
      2White matter hyperintesities
      3Cerebral microinfarction
      4Ischemic demyelination
      5Leukoaraiosis
      6White matter degeneration
      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”.
      • Kelley RE
      • Kelley BP.
      Ischemic demyelination.
      White matter lesion load is associated with is associated with brain atrophy beyond that expected with normal aging for both SVD and AD.
      • Habes M
      • Erus G
      • Toledo JB
      • et al.
      White matter hyperintensities and imaging patterns of brain ageing in the general population.
      In terms of pathogenesis, Brown et al
      • Brown WR
      • Moody DM
      • Thore CR
      • Anstrom JA
      • Challa VR.
      Vascular changes in the white matter in dementia.
      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.
      • Farrall AJ
      • Wardlaw JM.
      Blood-brain barrier: ageing and microvascular disease-systematic review and meta-analysis.
      Wong et al,
      • Wong SM
      • Jansen JFA
      • Zhang CE
      • et al.
      Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease.
      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.

      Roseborough A, Hachinski V, Whitehead. White matter degeneration-A treatable target?JAMA Neurology202077:793-794.

      VaD associated with hemorrhagic stroke

      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.
      • Planton M
      • Raposo N
      • Danet L
      • Albucher J-F
      • Peran P
      • Pariente J.
      Impact of spontaneous intracerebral hemorrhage on cognitive functioning: an update.
      Corraini et al
      • Corraini P
      • Henderson VW
      • Ording A
      • Pedersen L
      • Sorensen HT
      Long-term risk of dementia among survivors of ischemic or hemorrhagic stroke.
      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,
      • Garcia PY
      • Roussel M
      • Bugnicourt JM
      • et al.
      Cognitive impairment and dementia after Intracerebral haemorrhage: a cross sectional study of a hospital-based series.
      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,
      • Moulin S
      • Labreuche J
      • Bombois S
      • et al.
      Dementia risk after spontaneous intracerebral hemorrhage: a prospective cohort study.
      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
      • Biffi A
      • Bailey D
      • Anderson CD
      • et al.
      Rik factors associated with early vs delayed dementia after intracerebral hemorrhage.
      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,
      • Gottesman RF.
      Dementia after intracerebral hemorrhage.
      that lobar CMBs and presence of the APOE ε4 allele were also associated with delayed dementia. Pasi et al
      • Pasi M
      • Sugita BS
      • Xiong L
      • et al.
      Association of cerebral small vessel disease and cognitive decline after intracerebral hemorrhage.
      reported an enhanced risk of cognitive decline, following ICH, was associated with a higher global cerebral SVD score.
      It has been reported that pre-existing cognitive impairment often precedes ICH
      • Laible M
      • Horstmann S
      • Mohlenbruch M
      • Schueler S
      • Rizos T
      • Veltkamp R.
      Preexisting cognitive impairment in intracerebral haemorrhage.
      ,
      • Donnellan C
      • Werring D.
      Cognitive impairment before and after intracerebral hemorrhage: a systematic review.
      and this could be related to the presence of risk factors for cognitive decline at the time of the ICH
      • Benedictur MR Hochart A
      • Rossi C
      • et al.
      Prognostic factors for cognitive decline after intracerebral hemorrhage.
      which includes possible coexistent CAA.
      • Xiong L
      • Charidimou A
      • Pasi M
      • et al.
      Predictors for late post-intracerbral haemorrhage dementia in patients with probable cerebral amyloid angiopathy.
      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.
      • Ding J
      • Sigurosson S
      • Jonsson P
      • et al.
      Space and location of cerebral microbleeds, cognitive decline, and dementia in the community.
      The presence of dementia in CA-mediated lobar ICH is medium term predictor of 90-day mortality.
      • Jamieson EI
      • d Newman
      • Metcalf K
      • et al.
      Dementia is strongly associated with 90-day mortality in lobar cerebral amyloid angiopathy related intracerebral hemorrhage.
      In a Mayo Clinic Study of Aging,
      • Graff-Radford J
      • Arenaza-Urquijo EM
      • Knopman DS.
      White matter hyperintensities: relationship to amyloid and tau burden.
      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.
      • Kovari E
      • Herrmann FR
      • Hof PR
      • Bouras C.
      The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.
      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
      • Geraghty JR
      • Lara-Angulo MN
      • Spegar M
      • Reeh J
      • Testai F.
      Severe cognitive impairment in aneurysmal subarachnoid hemorrhage: Predictors and relationship to functional outcome.
      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.
      • Terpolilli NA
      • Feiler S
      • Dienel A
      • et al.
      Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.
      Shimamura et al
      • Shimamura N
      • Matsuda N
      • Satou J
      • Nakana T
      • Ohkuma H.
      Early ambulation produces favorable outcome and nondemented state in aneurysmal subarachnoid hemorrhage patients older than 70 years of age.
      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
      • Pendlebury ST
      • Rothwell PM.
      Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.
      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.
      • Iadecola C.
      The pathobiology of vascular dementia.
      SVD associated stroke is heritable 16% of the time
      • Malik R
      • Chauhan G
      • Traylor M
      • et al.
      MEGASTROKE Consortium. Multiancestory genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.
      and WMH is seen with a 50% heritable pattern.
      • Traylor M
      • Zhang CR
      • Adib-Samii P
      • et al.
      International Stroke Genetics Consortium. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.
      Of note, the MRI load of cerebral microvascular disease is exacerbated by those who carry the APOE ↋4 allele.
      • Wang R
      • Laveskog A
      • Laukka E
      • et al.
      MRI load of cerebral microvascular lesions and neurodegeneration, cognitive decline and dementia.
      A characteristic example of genetic-mediated SVD is CADASIL.
      • Marini SM
      • Anderson CD
      • Rosand J.
      Genetics of cerebral small vessel 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.
      • Auer DP
      • Putz B
      • Gossl C
      • Elbel G
      • Elbel G
      • Gasser T
      • Dichgans M.
      Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison.
      However, the specificity of such findings has been questioned.
      • Jouvent E
      • Duering M
      • Chabriat H.
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lessons from neuroimaging.
      Fig 3
      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.
      • Hara K
      • Shiga A
      • Fukutake T
      • et al.
      Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
      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.
      • Jen J
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      • et al.
      Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).
      SVD is also seen in CARASAL.
      • Giau VV
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      • An SSA
      • Kim SY.
      Genetic factors of cerebral small vessel disease and their potential clinical outcome.
      COL4 mutations can be related to intracerebral subcortical hemorrhages or microhemorrhages and severe SVD.
      • Campo-Caballero D
      • Rodriguez-Antiguedad JR
      • Eliza-Bazan J
      • et al.
      COL4A1 mutation as a cause of familial recurrent intracerebral hemorrhage.
      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.
      • Sondergaard CB
      • Nielsen JE
      • Hansen CK
      • Christensen H.
      Hereditary cerebal small vessel disease and stroke.
      Hereditary CAA, associated with both ischemic and hemorrhagic stroke, is associated with amyloid precursor protein (APP) mutations.
      Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia.
      The hereditary form tends to be more severe than sporadic CAA and a number of distinct and pathological features have been reported.
      • Kozberg MG
      • van Veluw SJ
      • Frosch MP
      • Greenberg SM.
      Hereditary cerebral amyloid angiopathy, Piedmont-type mutation.
      In terms of cerebral aneurysm with SAH, familial forms are well recognized
      • Leblanc R.
      Familial cerebral aneurysms.
      as well as an association with polycystic kidney disease and Ehlers-Danlos syndrome.
      • Samuel N
      • Radovanovic I.
      Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era.
      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).
      • Iadecola C
      • Duering M
      • Hachinski V
      • et al.
      Vascular cognitive impairment and dementia.
      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
      • Molad J
      • Kliper E
      • Korczyn AD
      • et al.
      Only white matter hyperintensities predicts Post-stroke cognitive performance among cerebral small vessel disease markers: Results from the TABASCO Study.
      with particular susceptibility from involvement of certain white matter tracts.

      Biesbroek JM, Weaver NA, Biessels GJ.Lesion location and cognitive impact of cerebral small vessel disease. Clin Sci (Lond)131:715-728.

      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.
      • ter Telgte A
      • Wiegertjes K
      • Gesierich B
      • et al.
      Temporal dynamics of cortical microinfarcts in cerebral small vessel disease.
      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.
      • DeReuck J
      • Auger F
      • Durieux N
      • et al.
      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 4
      Fig. 4FLAIR MRI brain scan a. and b. demonstrating diffuse atrophy, subcortical white matter hyperintensities and subcortical lacunar-type infarct .
      Fig 5
      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
      • Samaraweera APR
      • Falah Y
      • Pitiot A
      • Dineen RA
      • Morgan PS
      • Evangelous N.
      The MRI central vein marker; differentiating PPMS from RRMS and ischemic SVD.
      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.
      • Smith EE
      • Beaudin AE.
      New insights into cerebral small vessel disease and vascular cognitive impairment from MRI.
      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,
      • Ostojic J
      • Kozic D
      • Pavlovic A
      • et al.
      Hippocampal diffusion tensor imaging microstructural changes in vascular dementia.
      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.
      • Smith EE
      • Beaudin AE.
      New insights into cerebral small vessel disease and vascular cognitive impairment from MRI.
      ,
      • Alber J
      • Alladi S
      • Bae H-J
      • et al.
      White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.
      Fig 6:
      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.
      • Heiss W-D
      • Zimmermann-Mnzingen S.
      PET imaging in the differential diagnosis of vascular dementia.
      Subcortical involvement can also be detected supportive of associated cerebral SVD in VaD.
      • Heiss W-D.
      The additional value of PET in the assessment of cerebral small vessel Disease.

      Additional diagnostic assessment

      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.
      • Iadecola C
      • Duering M
      • Hachinski V
      • et al.
      Vascular cognitive impairment and dementia.
      ,
      • Van der Flier W
      • Skoog I
      • Schneider JA
      • et al.
      Vascular cognitive impairment.
      ,
      • Iadecola C
      • Yaffe K
      • Biller J
      • et al.
      Impact of hypertension on cognitive function: a scientific statement from the American Heart Association.
      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.
      • Walker KA
      • Power MC
      • Gottesman RF.
      Defining the relationship between hypertension, cognitive decline and dementia: A Review.
      The SPRINT MIND Investigators
      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,
      • Rapp SR
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      • Sachs BC
      • et al.
      Effects of intensive versus standard blood pressure control on domain-specific cognitive function.: a substudy of the SPRINT randomised controlled trial.
      no difference was seen in either memory or processing speed. Lane et al
      • Lane CA
      • Barnes J
      • Nicholas JM
      • et al.
      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,
      • Liu J
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      Causal impact of type 2 diabetes mellitus on cerebral small vessel disease: a Mendelian randomization analysis.
      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.
      • Gustavsson A-M
      • van Esten D
      • Stomrud E
      • Engstrom G
      • Nagga K
      • Hansson O.
      Midlife atherosclerosis and development of Alzheimer or vascular dementia.
      Intracranial atherosclerosis was found to have some association with MCI and dementia in the Atherosclerosis Risk in Communities ARIC) Study,
      • Dearborn JL
      • Zhang Y
      • Qiao Y
      • Suri MFK.
      Intracranial atherosclerosis and dementia: the atherosclerosis risk in communities (ARIC) study.
      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.
      • Satizabal CL
      • Beiser AS
      • Chouraki V
      • Chene G
      • Dufoull C
      • Seshadri S.
      Incidence of dementia over three decades of the Framingham Heart Study.
      However, in a comprehensive review of VaD,
      • Mijajlovic MD
      • Pavlovic A
      • Brainin M
      • et al.
      Post-stroke dementia – a comprehensive review.
      Mijajlovic et al point out that present treatment strategies are not convincingly demonstrated to be of value.
      There is support for an active physical and mental exercise program to prevent or delay progression of cognitive decline.
      • Livingston G
      • Huntley J
      • Summerlad A
      • et al.
      Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.
      Diet designed to reduce oxidative stress, such as the Mediterranean diet, may also help in protecting cognitive capacity.
      • Valls-Pedret C
      • Sala-Vila A
      • Serra-Mir M
      • et al.
      Mediterranean diet and age-related cognitive decline: a randomized clinical trial.
      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.

      with some studies reporting benefit for both donepezil and galantamine in VaD and mixed dementia.
      • Chen Y-d
      • Zhang J
      • Wang Y
      • Youan J-L
      • Hu W-L.
      Efficacy of cholinesterase inhibitors in vascular dementia: an updated meta-analysis.
      ,
      • Farooq MU
      • Min J
      • Goshgarian G
      • Gorelick PB.
      Pharmacotherapy for vascular cognitive impairment.
      There is reported potential benefit of rivastigmine in VaD,
      • Kandiah N
      • Pai M-C
      • Senanarong V
      • et al.
      Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia.
      but there have been some concerns raised about safety.
      • Noufi P
      • Khoury R
      • Jeyakumar S
      • Grossberg GT.
      Use of cholinesterase inhibitors in non-Alzheimer's dementias.
      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,
      • Olivares D
      • Deshpande V
      • Shi Y
      • et al.
      N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease.
      if any,
      • Farooq MU
      • Min J
      • Goshgarian G
      • Gorelick PB.
      Pharmacotherapy for vascular cognitive impairment.
      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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