Neuropharmacology 134 (2018) 226e239

Contents lists available at ScienceDirect

Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Invited review

The pathology and pathophysiology of vascular dementia

Raj N. Kalaria
Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne NE4 5PL, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus
Received 4 September 2017 and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological
Received in revised form and neuroimaging measures in life but more importantly pathological confirmation. Factors defining
13 December 2017
subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra
Accepted 18 December 2017
Available online 19 December 2017
and intracranial vessels and the anatomical location of tissue changes as well as time after the initial
vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes
of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence
Keywords:
Alzheimer's disease
worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis,
Cerebral amyloid angiopathy lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which
Cerebrovascular degeneration involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cere-
Dementia brum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease.
Neuropathology Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how
Small vessel disease arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and
Vascular dementia validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment
were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis
and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity,
VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction
and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly
define microvascular disease and vascular substrates of dementia.
This article is part of the Special Issue entitled ‘Cerebral Ischemia’.
© 2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
1.1. Definitions of vascular cognitive impairment, vascular cognitive disorder and VaD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
1.2. Stroke subtypes and clinical information on vascular causes of dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
1.3. Compatibility between clinically and pathologically diagnosed VaD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
1.4. Cerebrovascular pathology and brain parenchymal changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
1.5. Cerebral small vessel disease and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
1.6. Lacunes as a key factor in SVD type of VaD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
1.7. White matter lesions are strategic in SVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
1.8. Brain microinfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
1.9. Intracerebral microhaemorraghes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
1.10. Sporadic and hereditary cerebral amyloid angiopathies and the VaD syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
1.11. Familial small vessel diseases causing a VaD syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
1.12. Recent developments in clinicopathological correlation in VaD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
2. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

E-mail address: raj.kalaria@ncl.ac.uk.

https://doi.org/10.1016/j.neuropharm.2017.12.030
0028-3908/© 2017 Elsevier Ltd. All rights reserved.
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239 227

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

1. Introduction disease is equated with SVD in which hypertensive disease is

prominent (Rosenberg, 2017).
Worldwide cerebrovascular disease (CVD) is likely the most
common cause of cognitive impairment even above Alzheimer's
1.1. Definitions of vascular cognitive impairment, vascular cognitive
disease (AD). The most prominent form of CVD is ischaemic strokes
disorder and VaD
or cerebral ischaemic injury. Old age remains the strongest risk
factor for strokes and other types of CVD. CVD involves arterio-
The concept of VCI has been in use for more than 2 decades but
sclerotic changes in the cerebral or systemic vasculature, and often
it came into existence to empower an unique label for all condi-
both, that likely begin during a considerable period prior to the
tions of vascular origin or impaired brain perfusion VCI (Gorelick
manifestation of an overt stroke-like or CVD accident. While early
et al., 2011; Hachinski et al., 2006a; O'Brien et al., 2003). While
or subtle changes may not necessarily be recognised clinically, they
useful, it continually challenges how degrees of pathological
may be evident radiologically as white matter (WM) and silent
changes correlate with the degree of impaired cognition in the
lesions, mostly in form of lacunar infarcts. For example, 20% of
continuum of VCI. The description vascular cognitive disorder
healthy elderly people will bear magnetic resonance imaging
(Sachdev, 1999) also incorporates a continuum comprising cogni-
(MRI)-defined silent brain infarcts and up to 50% of these are
tive disorders of vascular aetiology with diverse pathologies and
detected in selected patient cohorts (Vermeer et al., 2007). Hy-
clinical manifestations. Therefore, in the most recent Diagnostic
pertensive small-vessel disease (SVD) is thought to be the main risk
and Statistical Manual of Mental Disorders (DSM) or DSM-V
factor for these infarcts, which may be associated with subtle def-
criteria and guidelines, categories of mild and major vascular
icits in physical and cognitive function that commonly go unno-
cognitive disorders were introduced (Association, 2013). Vascular
ticed, particularly in older age. In recent years, SVD has taken
cognitive disorder indicates a global diagnostic category, restrict-
precedence as a radiological concept (Wardlaw et al., 2013) and
ing the term VCI to patients whose cognitive impairment fell short
refers to an intracranial disorder which involves pathological
of dementia (Roman, 2002). The major neurocognitive disorder
changes within and at the surfaces of brain microvessels including
classification, meant to describe frank dementia as a substitute for
perforating arteries and arterioles, capillaries and venules. SVD
VaD appears to fit better with patients, and more adapted to
comprises tissue injury in both the cortical and subcortical grey and
neurodegenerative cognitive disorders for which memory
white matter. However, SVD often coexists with atherosclerosis
impairment is not predominant but comprises substantial frontal
involving large extracranial vessels and cardioembolic (CE) disease
lobe pathology (Sachdev et al., 2014). More recently, refinement
(Li et al., 2015).
towards a standardised diagnosis of VCI was attained in a Delphi
Vascular dementia (VaD) is widely regarded as the second most
analysis undertaken by a large group of clinicians and researchers
common type of dementia. VaD may culminate from global or focal
(Skrobot et al., 2017a, 2017b). This analysis conducted over six
effects of vascular disease. It is also characterised as a neuro-
survey rounds by the vascular impairment of cognition classifi-
cognitive disorder, which also incorporates behavioural symptoms,
cation consensus study (VICCCS) agreed to guidelines for the
locomotor abnormalities e.g. Parkinsonian-like gait disorder,
diagnosis of ‘Mild’ and ‘Major’ forms of VCI. The use of ‘Mild’ and
dysarthria and autonomic dysfunction. The relatively recently
‘Major’ subdivisions of the severity of impairment aligns with the
described umbrella term vascular cognitive impairment (VCI) en-
revised terminology in DSM-5. VICCCS also agreed that the Major
compasses all causes of CVD including hereditary forms that lead to
forms of VCI or VaD should be classified into four main subtypes
early and severe forms of dementia syndromes (Table 1). Within
including subcortical ischaemic vascular dementia or SIVaD, MID
the spectrum of CVD and VaD, the most common vascular
or cortical dementia, post-stroke dementia (PSD) and mixed de-
contributor to dementia is cerebral SVD (Wardlaw et al., 2013). As
mentias, which could be subdivided according to respective
the older population survives longer (Corraini et al., 2017; Sacco
neurodegenerative pathologies. VICCCS participants further
and Dong, 2014), VaD more often than not will involve the SVD
endorsed the National Institute of Neurological Disorders-
syndrome (Fig. 1).
Canadian Stroke Network neuropsychological assessment pro-
In this review, I mostly focus on cerebral SVD but also provide
tocols and recommendations for imaging (Skrobot et al., 2017b).
recent updates on the understanding of key vascular lesions and
Cognitive impairment or dementia following stroke is relatively
tissue changes, which contribute to dementia. It is clear that
common (Leys et al., 2005; Mok et al., 2017; Pendlebury and
despite the strong and unambiguous evidence that vascular factors
Rothwell, 2009). Incident dementia after stroke or PSD may
and vascular disease contribute to the global burden of brain dis-
develop within three months or after a stabilisation period of a
ease, dementia prognosis and research has mostly focused on AD.
year or longer after stroke injury (Allan et al., 2012; Bejot et al.,
Vascular causes of dementia and their contribution to neurode-
2011; Pohjasvaara et al., 1997). However, PSD can have a com-
generative processes have not been widely emphasised. The
plex aetiology with varying combinations of large artery disease
recognition of subtypes of clinical VaD (Table 1) was an important
(LAD) and SVD as well as non-vascular pathology. Stroke injury or
step forward towards current pathological classification based on
CVD may unmask other prexisting disease processes such as AD.
vascular aetiology. It was subsequently recognised that multi-
We have recently demonstrated that at least 75% of PSD cases
infarct dementia (MID) predominantly results from multiple large
fulfilling relevant clinical guidelines for VCI (Hachinski et al.,
cortical infarcts attributed to large vessel disease whereas dementia
2006b) are pathologically confirmed as VaD with little mostly
associated with subcortical ischemic lesions or Binswanger's dis-
age-related AD pathology (Allan et al., 2012). Moreover, the
ease involving subcortical structures and the WM results from
presence of any age-related hippocampal AD lesions did not
changes in intracranial small vessels. The older term Binswanger's
differentiate demented from non-demented post-stroke subjects
228 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239

Table 1
Common and less common causes of stroke pathophysiology associated with cognitive impairment and dementia.

Primary or Common conditions Vascular Distribution Predominant Tissue changes Form(s) of VaD/major VCDy
Secondary
Vascular
Disorder(s)*

Atherosclerotic Cardiac and carotid atherosclerosis Aorta, Carotid, Cortical and territorial infarcts; Large vessel dementia or
disease Intracranial- MCA WML multi-infarct dementia
branches
Aorta, coronary Infarcts, laminar necrosis, Hypoperfusive dementia
rarefaction
Embolic disease Cardioembolism Intracranial arteries, Large and small infarcts Multi-infarct dementia
MCA (MID)
Arteriolosclerosis Cerebral small vessel disease Perforating and Cortical infarcts, Small vessel dementia;
penetrating arteries, lacunar infarcts/lacunes, subcortical ischaemic
lenticulostriate arteries microinfarcts, WML vascular dementia; strategic
infarct dementia
Hypertensive vasculopathy Hypertensive
encephalopathy with
impairment; strategic
infarct dementia
Non- Arterial dissections (carotid, vertebral and intracranial), Vertebral, basilar, No pattern of brain infarctions: Minor VCI
atherosclerotic fibromuscular dysplasia, dolichoectatic basilar artery, large Branches of MCA, mural haemodynamic, thromboembolic,
non- artery kinking and coiling, radiation induced angiopathy, haematoma perforating or due to
inflammatory moyamoya disease artery; SVD occlusion of a perforating artery.
vasculopathies Subarachnoid haemorrhage;
lacunar infarcts, PVS
Aneurysms- sacular, berry, fusifom, cerebral Circle of Willis, Proximal Haemorrhagic infarcts, herniation Haemorrhagic dementia
branches of MCA, PCA
Vascular malformations: cavernous hemiangioma, Cortical lobes Rarefaction, WML Minor
arteriovenous, capillary
Cerebral venous thrombosis Venous sinus, Subcortical infarcts (thalamus),
periventricular veins lobar haemorrhages
Amyloid Hereditary CAAs (Amyloid b, prion protein, cystatin C, Leptomeninges, Cortical microinfarcts, Mild and Major VCI
angiopathies transthyretin, gelsolin) intracerebral arteries lacunar infarcts, WML
Monogenic stroke CADASIL, CARASIL, retinal vasculopathy with cerebral Leptomeningeal Lacunar infarcts/lacunes, Mild and Major VCI
disorders leukodystrophies (RVCLs), Moyamoya disease, Hereditary arteries, intracerebral microinfarcts, WML
angiopathy, nephropathy, aneurysm and muscle cramps subcortical arteries
(HANAC), COL4 disorders
Monogenic Fabry disease, familial hemiplegic migraine, hereditary Branching arteries Cortical and subcortical infarcts, Mild and Major VCI
disorders haemorrhagic telangiectasia, Vascular Ehlers-Danlos haemorraghic infarcts
involving syndrome, Marfan syndrome, Psuedoxanthoma elasticum,
stroke Arterial tortuosity syndrome, Loeys-Dietz syndrome,
polycystic kidney disease; Neurofibromatosis type 1 (von
Ricklinghausen disease), Carney syndrome (Facial
lentiginosis and myxoma)
Metabolic Mitochondrial disorders (MELAS, MERRF, Leigh's disease, Intracerebral small Cortical and subcortical stroke-like Mild VCI
disorders MIRAS), Menkes disease, Homocystinuria, Tangier's disease arteries, territorial lesions, microcystic cavitation,
arteries cortical petechial haemorrahges,
gliosis, WML
Haematological Paraproteinaemia, coagulopathies (antiphospholipid Large and intracerebral Cortical and subcortical infarcts, Mild VCI
disorders antibodies, SLE, nephrotic syndrome, Sneddon syndrome, arteries ICH and subarachnoid
deficiencies in clotting cascade factors e.g. protein S, C, Z, haemorrhages
antithrombin III, plasminogen)
Vasospastic Subarachnoid haemorrahge, Migraine related strokes, Intracranial arteries, Cortical and subcortical small Mild VCI
disorders paroxysmal hypertension, drug induced vasconstriction MCA infarcts

Data summarised and updated from several source references (Caplan, 2008; Ferro et al., 2010; Filosto et al., 2007; Kalaria, 2016; Kalaria et al., 2015). Several disorders may
also occur with other co-morbidities such as coronary artery disease, congestive heart failure, hypertension, diabetes, hyperlipidaemia, hypercoagulability, renal disease, atrial
fibrillation and valvular heart disease. *Other miscellaneous causes of stroke including mechanical, invention induced or rare genetic syndromes such as trauma, iatrogenic,
decompression sickness, air or fat embolism, transplantation and Werner's syndrome can lead to cognitive impairment. yVCI determined as Mild or Major forms when two or
more cognitive domains are affected per minimal harmonization guidelines or per VCD (Hachinski et al., 2006a; Sachdev et al., 2014; Skrobot et al., 2016). Abbreviations: CAA,
cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL; cerebral autosomal recessive
arteriopathy with subcortical infarcts and leukoencephalopathy; COL4, Collagen IV; ICH, intracerebral haemorrhage; MCA, middle cerebral artery; MELAS, Mitochondrial
Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like Episodes; MERRF, Myoclonic epilepsy with ragged red fibres; MIRAS; PCA, posterior cerebral artery; PVS, peri-
vascular spaces; SLE, systemic lupus erythematosus; SVD, small vessel disease; VaD, vascular dementia; VCD, vascular cognitive disorder; VCI, vascular cognitive impairment;
WML, white matter lesion.

(Akinyemi et al., 2017).
1.2. Stroke subtypes and clinical information on vascular causes of
dementia
In recent years, the classification systems for stroke have
enabled better understanding of the pathophysiology of CVD,
particularly with a view to identifying precise substrates of cogni-
tive impairment and reducing recurrent vascular brain injury.
These systems have provided knowledge on the frequencies of
ischaemic strokes in hospital and community based settings (Fig. 1).
While none of the stroke subtype classification systems is perfect
(Amarenco et al., 2009; McArdle et al., 2014), the Trial of Org 10172
in Acute Stroke Treatment (TOAST) has been widely utilised for
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
Fig. 1. Proportions of stroke subtypes and cerebrovascular pathologies associated
with VaD. 1A, Stroke subtypes according to TOAST (Adams et al., 1993). Chart shows
proportions of stroke pathophysiology collated from 13 different studies involving
12,931 patients from both hospital and non-hospital or community based cohorts in
Western Europe and USA (Alzamora et al., 2008; Bejot et al., 2008; Bogiatzi et al., 2014;
Gulli et al., 2016; Hajat et al., 2011; Ihle-Hansen et al., 2012; Kolominsky-Rabas et al.,
2001; Marnane et al., 2010; Palm et al., 2012; Petty et al., 1999; Saposnik et al., 2000;
Schulz and Rothwell, 2003; Tsai et al., 2013). Figures show mean percent of strokes
resulting from large artery disease (LAD), CE, cardioembolic (CE), lacunar infarction or
small vessel disease (SVD), other (Other) and undermined (Und) causes. CE is the most
common cause of strokes with SVD a little less frequent. Patients with CE having small
infarcts commonly develop VaD. The frequency of ICH in these cohorts was a mean of
15% (range 9.6e14%). 1B, Different cerebrovascular pathologies as outcomes of clini-
cally diagnosed VaD. Currently reported studies (and unpublished data) show that the
estimated % cases for the three principal subtypes are as follows: Subtype I, 20e40%;
subtype II, 40e50% and subtype III, 10e15% with estimated 5% or rare types such as
hereditary cases involving haemorrhages and large and small vessel diseases. Subtype I
may result from large vessel occlusion atherothromboembolism, artery-to-artery
embolism or cardioembolism (CE). Subtype II usually involves descriptions of arte-
riolosclerosis, lipohyalinosis, hypertensive, arteriosclerotic, amyloid or collagen angi-
opathy. Subtype III is caused by infarcts in the ‘strategic’ areas such as the thalamus
and hippocampus and may involve several risk factors including CE and intracranial
SVD. The risk factors associated with particularly Subtype I are varied including hy-
pertension, carotid artery atherosclerosis, CE (cause mostly atrial fibrillation) and
coronary artery disease. Subtype II may involve hypertension, diabetes mellitus,
hyperlipidaemia, hyperhomocysteinaemia, chronic kidney disease, infection and
obstructive sleep aponea. Lifestyle factors such as smoking, obesity and alcohol abuse
are other factors. These subtypes would include dementia among post-stroke survivors
who fulfil the National Institute of Neurological Disorders and Stroke and Association
Internationale pour la Recherche  et l'Enseignement en Neurosciences (NINDS-AIREN)
criteria for probable vascular dementia (Roman et al., 1993). Abbreviations: CE, car-
dioembolic; LAD, large artery disease; LVD, large vessel disease; SVD, small vessel
disease; TOAST, Trial of Org 10172 in Acute Stroke Treatment; Und, undetermined.
evaluating the pathophysiology of clinical stroke. The TOAST clas-
sification (Adams et al., 1993) suggests atherosclerotic or LAD and
CE diseases are the main causes of infarctions associated with major
arterial territories, which may be admixed in cortical and subcor-
tical regions (Fig. 1A; Table 2). Thromboembolic events are
responsible for up to 50% of all ischaemic strokes whereas intra-
cranial SVD causes 20-25% of the infarcts (Fig. 2). SVD rather than
LAD appears to be more common in non-white populations (Gulli
229
et al., 2016; Tsai et al., 2013). Strokes of undetermined causes are
identified most frequently but this category may contain several
cases admixed with small artery occlusion (Bogiatzi et al., 2014;
Marnane et al., 2010). Complicated angiopathies such as fibro-
muscular dysplasia, arterial dissections, granulomatous angiitis,
collagen vascular disease and giant-cell arteritis are rarer causes of
CVD and likely become categorised as stroke subtypes of under-
mined cause. They are rarer causes of VaD (Table 1). The distribu-
tions of the clinical subtypes are also evident in unbiased
pathological cohorts (Deramecourt et al., 2012; Grinberg and Thal,
2010). Small vessel alternations are very common and mostly
involve arteriolosclerosis. They are associated with lacunar infarcts
predominantly occurring in the WM, basal ganglia and thalamus.
WM disease or subcortical leukoencephalopathy with incomplete
infarction is a common pathological change associated with de-
mentia (Deramecourt et al., 2012). Others features include bor-
derzone (watershed) infarctions, laminar necrosis and cerebral
amyloid angiopathy (CAA) (Fig. 2).
Review of the medical notes of patients who have died with
strokes or other forms of CVD provides insight into the nature of
clinical progression, identifies arterial territories linked to any
patterns of changes in cognition or behaviour. Upon evaluation of
clinical information including history, timing of event, neuro-
psychometric tests and neuroimaging features of the DSM criteria
are mostly widely applied to define presence of dementia. In the
DSM-IV and earlier versions of DSM criteria, diagnosis of dementia
placed emphasis on memory loss as a core feature. However, many
patients with VaD will not necessarily exhibit overt memory defi-
cits, particularly in the early stages. They predominantly develop a
frontal dysexecutive syndrome (Desmond, 2004). This shortfall
would be overcome in the proposed guidelines for recognition of
minor and major VCI or vascular cognitive disorder, which con-
centrates on speed of information processing, complex attention
and frontal-executive functioning (Sachdev et al., 2014; Skrobot
et al., 2017b). The wider use of the Montreal Cognitive Assess-
ment (MoCA) over the MMSE as a preferred first cognitive
screening instrument in CVD cases has also been encouraged. Both
the full and short versions of the MoCA appear to have reasonable
diagnostic accuracy in discriminating in terms of sensitivity and
specificity against the MMSE (Freitas et al., 2012).
1.3. Compatibility between clinically and pathologically diagnosed
VaD
As with all other dementias, confirmation of VaD diagnosis is
definitive at post-mortem (Fig. 1B). Relevant sampling of both ce-
rebral hemispheres and neuropathological examination (Hachinski
et al., 2006a) are necessary to rule out significant pathological
changes associated with other dementias. The prevalence of early-
onset VaD (<65 years old) ranges from 3% to 44% in various clinic
and population-based studies (Vieira et al., 2013). In a recent US
study among medicare recipients, VaD prevalence was ~15%
(Goodman et al., 2017). However, these values may not reflect true
prevalence and incidence rates of VaD due to inconsistencies in
diagnostic criteria, sampling methods and variations in subject or
country demographics, morbidity and mortality trends. When a
range of clinical criteria was applied to sample sizes of 59 to 1,929,
autopsy studies revealed pathologically diagnosed VaD is as low as
0.03% to as high as 60% with an overall mean estimate of 18%
(Jellinger, 2008; Kalaria, 2016). In developed countries, estimated
rates of pathologically diagnosed VaD as defined by various criteria
lie between 8 and 15%. In studies where diagnosis was restricted to
the widely used NINDS-AIREN criteria (Roman et al., 1993), fre-
quencies are reported to be ~7%. Taking the above estimates into
consideration the worldwide frequency of VaD in autopsy verified
230 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239

Table 2
Key Lesions in CVD for Neuropathological diagnosis of VaD.

Key variables for pathological diagnosis:

 Ischaemic or haemorhagic infarct(s)
 Is the haemorrhagic lesion(s) a major component?
Atherosclerosis/atheroma Disease:*
 Presence in medium-sized to large arteries at the base of the brain, characterised by formation of plaques showing varying degrees of destruction of the vessel wall and
accumulation of lymphocytes and macrophages;
 Later stages plaques may contain necrotic core, cholesterol clefts and foci of calcification.
Microscopic vascular changes:y
 Arteriolosclerosis: Hyaline thickening of walls of vessels 0.5 mm in diameter, not associated with lipid-containing cells replacing the tunica media. Diagnosis requires an
absence of intramural inflammation, amyloid or fibrinoid necrosis.
 Microvascular protein deposition (e.g. CAA)
 Other microangiopathies, venous collagenosis
Parenchymal changes:y
 Large infarcts: Maximum diameter 50 mm
 Small or Lacunar infarcts: cystic lesion visible to the naked eye but 1 cm in diameter
 Microinfarcts: Ischaemic lesions found on microscopic examination (50-500 mm).
 Large haemorrhage: Haemorrhagic lesion visible to the naked eye, which is easily identifiable on macroscopic examination.
 Microhaemorrhage: Haemorrhagic lesion (with parenchymal involvement) found on microscopic examination.
 White matter pallor: A reduction in myelin staining in white matter in Luxol fast blue stained sections.
 White matter rarefaction - weakly stained/pale and loose appearance of myelinated fibres.

*Adapted from VCI Neuropathology guidelines criteria (Deramecourt et al., 2012; Skrobot et al., 2016; Strozyk et al., 2010). The protocol for examination of brains from CVD
subjects is essentially similar to that for any other disease (Kalaria, 2016). yFor reporting purposes, further details on pathological examination (Kalaria, 2016) can be scored
numerically to provide a summary (Hachinski et al., 2006a). For example, 0 is absent and 1 means present. Less frequent lesions including watershed infarcts and laminar
necrosis. Increasing numerical value may also be assigned to the infarcts. Abbreviations: CAA, cerebral amyloid angiopathy; VCI, vascular cognitive impairment; WM, white
matter.

cases calculates to 10-15%, being marginally less than when clinical
criteria alone were used (Barker et al., 2002; Knopman et al., 2003).
In Japan, the incidence of autopsy verified VaD was 35% (Seno et al.,
1999) and later reported to be 22% (Akatsu et al., 2002). Population-
based cohorts should provide the best estimates for pathology
verified VaD. However, there are only few such studies and they all
show that microvascular lesions occur more frequently than
neurodegenerative lesions in elderly community dwelling subjects
with dementia (CFAS, 2001; Schneider et al., 2007; Sonnen et al.,
2007; White et al., 2005). Despite such prospective studies, actual
frequencies will depend on which subtype of ischaemic stroke or
CVD is diagnosed clinically and followed up to post-mortem.
1.4. Cerebrovascular pathology and brain parenchymal changes
Few studies have recorded precise ischaemic, oedematous and
haemorrhagic lesions induced by pathological changes in the brain
circulation or perfusion to be associated with VaD. For example, a
summary from ten different studies where VaD was diagnosed
clinically (Roman et al., 1993) indicated that in 78% of the subjects
cortical and subcortical infarcts including incomplete and border-
zone infarcts were important factors. Among other lesions SVD was
common with nearly 50% showing lacunar infarcts or microinfarcts
(Table 2). Moderate to severe CAA was present in ~10% of the cases.
Hippocampal sclerosis and cell atrophy, which may be caused by
remote ischaemic injury, was apparent in 55% of the cases in one
study with clinical diagnosis of ischaemic VaD (Vinters et al., 2000).
In an attempt to evaluate the natural history and staging of CVD, we
proposed that vessel wall modifications such as arteriolosclerosis
or CAA were the most common and earliest changes. These were
followed by perivascular spacing with lacunar and regional
microinfarcts infarcts occurring as consequent but independent
processes. The regional progression of the changes were fron-
tal > temporal lobe  basal ganglia. In dementia subjects, VaD had
the highest total scores of vascular pathology whereas AD was the
second and Dementia with Lewy Bodies as the last but greater than
ageing controls (Deramecourt et al., 2012).
1.5. Cerebral small vessel disease and pathophysiology
SVD entails fibroid necrosis, hyalinization of vessels, and
expansion of the perivascular space and pallor of adjacent peri-
vascular myelin, with associated astrocytic gliosis (Fig. 3). The
smaller vessels of the brain including intracerebral end-arteries and
arterioles undergo progressive age-related changes (Lammie et al.,
1997), which alter perfusion and cause lacunar infarcts (cystic le-
sions generally <1cm) and microinfarcts (Table 2). The arteriolar
changes range from wall thickening by hyalinosis, reduction or
increment of the intima to severe arteriolosclerosis and fibroid
necrosis. Arteriolosclerotic changes likely promote loss of elasticity
to dilate and constrict in response to variations of systemic blood
pressure or auto-regulation, which in turn causes fluctuations in
blood flow response and changes in tissue perfusion. The deep
cerebral structures and WM would be rendered most vulnerable
because the vessels are end arteries almost devoid of anastomoses
(Fig. 4). Small vessel pathology likely leads to oedema and damage
of the blood-brain barrier (BBB) with chronic leakage of fluid and
macromolecules in the WM (Giwa et al., 2012; Ho and Garcia, 2000;
Wardlaw, 2010). Hypertension linked SVD would promote
decreased production and increased degradation of nitric oxide
resulting in endothelial dysfunction. Microvascular disease is
further associated with degrees of inflammation including the
presence of lymphocytes or macrophages localised on blood vessels
(and not necessarily a function of brain ischemia). In very old SVD
subjects, there is often evidence of remote haemorrhage in form of
perivascular hemosiderin (Deramecourt et al., 2012).
1.6. Lacunes as a key factor in SVD type of VaD
Lacunar infarcts are a strong substrate of VaD (Fig. 3). They
represent small foci of ischaemic necrosis resulting from narrowing
or occlusion of penetrating arteries branching directly from larger
cerebral arteries (Fisher, 1982). Lacunar infarcts are frequently
multiple and bilateral and often coexist with other vascular lesions
(e.g. large infarcts or diffuse WM damage). Whether single or
multiple, they may be asymptomatic, depending on their location
and the volume of normal brain tissue lost. Lacunes may represent
small haemorrhages, dilated perivascular spaces, or even as healed
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239 231

Fig. 2. Pathological changes found in stroke involving large artery and small vessel diseases. These are often found in AD besides VaD/VCI. A, Small infarcts (arrows) in the
occipital lobe of 80-year old woman with cognitive impairment. This fits the classification of Subtype I in Fig. 1. B: Lacunes (arrow) and WM lesions in external capsule in the basal
ganglia of a 78-year-old man with cognitive impairment. Note also WM rarefaction in the temporal limb. C: Perivascular spaces (dilatation) and demyelination in WM (Luxol fast
blue stain). D, Microinfarct and necrotic parenchyma (arrow) in the frontal cortex (H&E). E, CAA demonstrated by Ab immunoreactivity in the frontal cortex. Ab reactivity can also
been seen in the glial limitans (arrow). F, arteriolosclerotic vessel with features of hyalinsation and fibroid necrosis (H&E). Magnification Bar: A, B ¼ 2cm; C-D ¼ 50mm, E-F ¼ 100 mm.

or re-absorbed minute or petechial haemorrhages. Microlacunes
have also been described which essentially should be thought of as
large cystic microinfarcts.
Apart from critical lesions occurring often in the internal capsule
or caudate nucleus, a recent meta-analyses concluded there were
no pathological differences between symptomatic and asymp-
tomatic patients. Perivascular oedema and thickening,
inflammation and disintegration of the arteriolar wall were com-
mon, whereas vessel occlusion was rare (Bailey et al., 2012), In
neuropathological cases without evidence of AD or other neuro-
degenerative pathologies, dementia was associated with severe
cribriform change and subcortical WM damage and microinfarcts
(Esiri et al., 1997; Strozyk et al., 2010). In the Honolulu-Asia Aging
Study analysis (White, 2009), microvascular infarcts (lacunar and
232 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
Fig. 3. Different Cerebrovascular Pathologies associated with Dementia in cerebral
SVD. Schematic diagram of the coronal plane at the level of the basal ganglia. The
lesions are equivalent to the Newcastle categorisation of subtypes II (Kalaria et al.,
2004). In all of above, the age of the vascular lesion(s) should correspond with the
time when disease began. SVD comprises descriptions of arteriosclerosis, lip-
ohyalinosis, hypertensive, arteriosclerotic, amyloid or collagen angiopathy. The
numbers correspond to the following changes: 1, Periventricular lesions in WM; 2,
Subcortical infarcts. lacunes; 3, Cortical infarcts: Small infarcts; 4, Subcortical and
cortical microinfarcts; 5, Microhaemorrhages and microbleeds; 6, CAA in lep-
tomeningeal vessels; 7, Superficial siderosis (various causes). Abbreviations: CCA, ce-
rebral amyloid angiopathy; SVD, small vessel disease.
microinfarcts) were identified as the sole or dominant lesion in 34%
of the definitely impaired decedents. Only leukoencephalopathy
was associated with dementia, and large infarcts were associated
with VaD. VaD without significant AD pathology showed more
severe cribriform change and deep white and grey matter lacunar
or microinfarcts than did stroke subjects with macroscopic infarcts
and elderly subjects without dementia (Smallwood et al., 2012).
Similarly, lacunar infarcts and microinfarcts were the most com-
mon neuropathological features in more than 50% of elderly pa-
tients with ischaemic VaD (Vinters et al., 2000) and also strong
determinants of dementia in the Geneva brain ageing study
(Giannakopoulos et al., 2007). However, these findings were often
accompanied by moderate to severe atherosclerosis (Fig. 2).
1.7. White matter lesions are strategic in SVD
White matter lesions (WMLs) incorporate WM rarefaction,
incomplete infarction, lacunar strokes, perivascular spacing and
demyelination but sometimes also axonal degeneration (Fig. 2).
Both in areas of leukoaraiosis and zones outside, the lesions show
decreased vascular density indicating that leukoaraiosis appears a
generalised feature of CVD rather than limited to deep the WM.
This is consistent with finding of an association with unstable ca-
rotid plaques and the number of WM lesions, suggesting a
thromboembolic role in some patients with leukoaraiosis (Altaf
et al., 2006).
Neuroimaging and pathological studies demonstrating WM
hyperintensisties represent degeneration of the WM mostly
explained by SVD (Pantoni, 2010; Pantoni and Garcia, 1997; Strozyk
et al., 2010). Diffuse and focal WM lesions are a hallmark of VaD
(Ihara et al., 2010) but also occur most in ~30% of AD and dementia
with Lewy body (DLB) cases (Englund, 1998). There is some con-
troversy whether deep or periventricular lesions are of more
importance but this depends on the definition of boundaries be-
tween the periventricular and deep WM if the coursing of the fibres
is used as markers (Kovari et al., 2007). Lacunar infarcts are pro-
duced when the ischaemic damage is focal and of sufficient severity
to result in a small area of necrosis, whereas diffuse WM change is
considered a form of rarefaction or incomplete infarction where
there may be selective damage to some cellular components.
Although the U-fibres are usually spared WM disease comprises
several patterns of alterations including pallor or swelling of
myelin, loss of oligodendrocytes, damage to axons, cavitations with
or without presence of macrophages and areas of reactive astro-
gliosis (Simpson et al., 2007), where the astrocytic cytoplasm and
cell processes may be visible with standard stains. Oligodendro-
cytes are particularly vulnerable to hypoxic environment created by
low perfusion, which in turn may differentially affect myelin as
indicated by the remarkable reduction the ratio of myelin-
associated glycoprotein (MAG) to proteolipid protein 1 (PLP1) not
only in the WM but also the cerebral cortex in VaD (Barker et al.,
2014; Thomas et al., 2015).
Lesions in the WM also include spongiosis i.e. vacuolisation of
the WM structures and widening of the perivascular spaces
(Yamamoto et al., 2009). Affected regions do not have sharp
boundaries, in contrast to the plaques of multiple sclerosis. These
changes may be associated with chronic pro-thrombotic endothe-
lial dysfunction in cerebral SVD (Hassan et al., 2003) also involving
the WM (Brown and Thore, 2011). There may be a cerebral response
to the SVD by increasing endothelial thrombomodulin (Giwa et al.,
2012). The projected misery perfusion due to capillary loss or ab-
normalities occurring prior to leukoaraiosis corroborates the
finding of a chronic hypoxic state in the deep WM (Fernando et al.,
2006), which releases several growth promoting factors (Simpson
et al., 2009). Some of the WM damage in demented patients may
simply reflect Wallerian changes secondary to cortical loss of
neurons. However, histological changes characteristic of Wallerian
degeneration are not readily evident as WM pallor. Moreover, we
surprisingly found even in lesional deep WM as defined by MRI,
there was relative axonal preservation as assessed by 3D stereo-
logical methods (Highley et al., 2014). Conversely, in AD patients
with severe loss of cortical neurons similar WM lesions were not
apparent (Englund, 1998).
While WM changes focus on the arterial system, narrowing and,
in many cases, occlusion of veins and venules by collagenous
thickening of the vessel walls also occur. The thickening of the walls
of periventricular veins and venules by collagen (collagenosis) in-
creases with age, and perivenous collagenosis is increased further
in brains with leukoaraiosis (Brown et al., 2002b). The presence of
apoptotic cells in WM adjacent to areas of leukoaraiosis suggests
that such lesions are dynamic, with progressive cell loss and
expansion (Brown et al., 2002b). Vascular stenosis caused by col-
lagenosis may induce chronic ischemia or oedema in the deep WM
leading to capillary loss and more widespread effects on the brain
(Brown and Thore, 2011).
1.8. Brain microinfarction
The accumulation of small, even miniscule ischaemic lesions as
an important substrate of cognitive impairment and dementia has
been emphasised in recent years (Arvanitakis et al., 2011a; Brundel
et al., 2012; Kalaria, 2012; Launer et al., 2011). Microvascular in-
farcts (lacunar infarcts and microinfarcts) also predict poor
outcome in the elderly (Ballard et al., 2000; Brown et al., 2002a;
Vinters et al., 2000). In the Honolulu- Asia Aging Study, the
importance of microvascular lesions as a likely explanation for
dementia was nearly equal to that of Alzheimer lesions (White,
2009; White et al., 2002). Microinfarcts are described as attenu-
ated lesions of indistinct nature occurring in both cortical and
subcortical regions and of up to 500 mm diameter (Figs. 2 and 3;
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239 233

Fig. 4. Schematic of Penetrating Artery in Normal and SVD Subjects. In SVD, progressive vascular changes linked to hypertensive disease and hereditary non-amyloid or amyloid
angiopathies lead to parenchymal changes. The key consequences of vessels changes impact on the neurons in the grey matter, oligodendrocytes and myelin loss in WM, which
leads to increased perivascular spacing, lacunar infarcts and microinfarction and rarely microbleeds from the capillaries. WM changes are likely caused by an hypoxic environment
promoted by obstruction or blockage of the artery proximally to affect the deep WM. WM degeneration may lead to development of lacunar infarcts at the edge of WM changes
(Duering et al., 2013). In VaD cases, where CAA was noted lack of clearance of amyloid b may accumulate with the branching vessels proximally that exhibits as leptomeningeal CAA,
one of the 7 pathologies related to cognitive impairment (Skrobot et al., 2016). Abbreviations: SVD, small vessel disease.

Table 2). These foci exhibit usually a small vessel, pallor, peri-
vascular neuronal loss, axonal damage (WM) and gliosis. They are
estimated to occur in thousands (Westover et al., 2013) and typi-
cally present in at least 30% of the CVD sample which comes to
autopsy (Arvanitakis et al., 2011a). Such lesions or combinations of
these are reported when there are multiple or greater than three
present in any region (Table 2).
Microinfarcts in both cortical and subcortical structures have
been evaluated as substrates of cognitive impairment (Arvanitakis
et al., 2011a; Kalaria, 2012; Kovari et al., 2004; Launer et al.,
2011). Overall, multiple cortical microinfarcts are associated with
greater odds of dementia. In one of the original studies (Kovari
et al., 2004), cortical microinfarcts were found to be the best pre-
dictor of cognitive deficits, whereas periventricular and diffuse
deep WM demyelination accounted for lesser clinical dementia
rating variability in brain aging. After controlling for amyloid b
deposition, cortical microinfarcts and to lesser extent periven-
tricular demyelination were also associated with cognitive decline
in individuals at high risk for dementia (Kovari et al., 2007). Simi-
larly, multiple cortical microinfarcts were associated with wors-
ening semantic memory and perceptual speed (Arvanitakis et al.,
2011a). In the most recent Cognitive Function in Ageing Study
(CFAS), whereas cortical microinfarcts were related to greater deep
WM lesion scores microinfarcts in subcortical regions were related
to periventricular lesions (Ince et al., 2017). This suggests the pre-
dilection for microinfarction is brain region specific and could not
only be influenced by the type of WM change but also the nature of
vascular pathology. This is entirely consistent with the findings
(Kovari et al., 2017) that vascular pathologies other than structural
microangiopathy, including arterial hypotension or large vessel
atherosclerosis may play a role in the development of microinfarcts.
Cortical microinfarcts are increased in the presence of CAA
(Okamoto et al., 2012) and commonly found in tandem with CAA in
the occipital cortex (Kovari et al., 2017). In another study, cortical
microinfarcts were frequently detected in AD and associated with
CAA but rarely observed in subcortical VaD linked to SVD (Okamoto
et al., 2009; Suter et al., 2002). Indeed, microinfarcts in the cerebral
cortex associated with severe CAA may be the primary pathological
substrate in a significant proportion of VaD (Haglund et al., 2006). It
is also proposed that changes in hemodynamics e.g., hypotension
and atherosclerosis may play a strong role in the genesis of cortical
watershed microinfarcts.
1.9. Intracerebral microhaemorraghes
Stroke subtype classification suggests intracerebral haemor-
rhages (ICH) occur in 12% of all stroke patients (Fig. 1A). However,
cerebral microhaemorrhages may be present in many cases
without ICH. Cerebral microhaemorrhages or microbleeds detected
by MRI are small, dot like hypotense abnormalities, and have been
associated with extravasated haemosiderin derived from erythro-
cytes, lipohyalinosis and CAA (Fazekas et al., 1999). They are likely a
234 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
surrogate marker of SVD evident on MRI along with lacunes and
WM changes (Van der Flier and Cordonnier, 2012). The prevalence
of radiological microbleeds in VaD ranges 35%-85%. Microbleeds are
mainly thought to result from hypertensive vasculopathy, but the
frequent co-occurrence of lobar microbleeds suggests that neuro-
degenerative pathology or CAA is also of importance (Werring et al.,
2011). The relevance of this radiological construct is increasingly
recognised due to their relation to clinical outcome and occurrence
in anti-amyloid vaccination trials (Greenberg et al., 2009). How-
ever, the presence of multiple microbleeds in the context of VaD is
related to worse performance on cognitive tests, mainly in psy-
chomotor speed and executive functioning. Microbleeds are com-
mon in cognitively normal older individuals but attribution of these
to VaD, should follow careful exclusion of other causes of cognitive
impairment and only if numerous such lesions are present.
Both radiological cerebral microbleeds and foci of haemosiderin
containing single crystalloids or larger perivascular aggregates are
found in brains of older subjects including those diagnosed with
VaD and AD but the radiological and pathological relationship be-
tween these findings has not been entirely clear. Recent evidence
suggests that cerebral microbleeds detected by MR imaging are a
surrogate for ischaemic SVD rather than exclusively haemorrhagic
diathesis (Janaway et al., 2014). Greater putamen haemosiderin was
significantly associated with indices of small vessel ischemia
including microinfarcts, arteriolosclerosis and perivascular spacing
and with lacunes in any brain region but not LAD, or whole brain
measures of neurodegenerative pathology. Higher levels of puta-
men haemosiderin were correlated with more microbleeds upon
MR imaging but it is possible that brain iron homeostasis and small
vessel ischaemic change are responsible for these rather than only
as a marker for minor episodes of cerebrovascular extravasation.
1.10. Sporadic and hereditary cerebral amyloid angiopathies and
the VaD syndrome
CAA occurs most commonly in AD (Attems et al., 2011;
Charidimou et al., 2012; Grinberg and Thal, 2010; Love et al.,
2015) but it is often found in CVD in the absence of AD pathology
(Cohen et al., 1997). CAA is an independent substrate for cognitive
impairment and contributes to cognitive dysfunction (Arvanitakis
et al., 2011b; Pfeifer et al., 2002). Tissue microstructural damage
caused by CAA prior to pre-ICH is independently associated with
cognitive impairment (Viswanathan et al., 2008). The prevalence of
CAA in VaD is not known but it is a major cause of intracerebral and
lobar haemorrhages leading to profound ischaemic damage
(Reijmer et al., 2015) (Fig. 3). Several familial forms of CAA involving
ischaemic and haemorrhagic infarcts (see below) and cerebral
hypoperfusion testify to the link between CAA and VaD. In a study
of surgical biopsies exhibiting cerebral and cerebellar infarction,
CAA was significantly more common in samples showing infarction
than in age-matched controls with non-vascular lesions (Cadavid
et al., 2000). There is also an association between severe CAA and
cerebrovascular lesions coexisting with AD, including lacunar in-
farcts, microinfarcts and haemorrhages (Ellis et al., 1996; Okamoto
et al., 2012; Olichney et al., 1995). This association apparently is not
attributable to apolipoprotein E (APOE) ε4 allele, as the vascular
lesions correlated best with severity of CAA, regardless of genotype
(Grinberg and Thal, 2010; Olichney et al., 2000). There is also some
evidence to suggest CAA is related to WM changes but not exclu-
sively in the oldest old (Tanskanen et al., 2013). The first stroke-like
episode triggers multiple cerebral bleeds preceded by diffuse WM
changes that in turn lead to rapid decline of cognitive functions.
There are more than 10 different hereditary CAAs caused by
mutations in different genes (Revesz et al., 2009; Yamamoto et al.,
2011). All these angiopathies lead to VCI or VaD. They are
characterised by multiple haemorrhages and haemorrhagic or
ischaemic infarcts in addition to severe amyloid deposition within
walls of the meningeal and intracerebral vessels. In hereditary ce-
rebral haemorrhage with amyloidosis of the Dutch type, dementia
occurs in most patients surviving their initial stroke (Haan et al.,
1990) and may occasionally be the presenting feature
(Wattendorff et al., 1982). The extensive CAA is alone sufficient to
cause dementia and this has implications for CAA related cognitive
dysfunction in sporadic CAA and AD (Natte et al., 2001). In the
Icelandic type of hereditary cerebral haemorrhage with amyloid-
osis (HCHWA-I) which is associated with a point mutation in the
Cystatin C gene (Levy et al., 1989) dementia has been attributed to
the multiple vascular lesions. Individuals with gelsolin-related
amyloidosis manifest facial palsy, mild peripheral neuropathy and
corneal lattice dystrophy; atrophic bulbar palsy, gait ataxia and
mild cognitive impairment (Kiuru et al., 1999). Familial British de-
mentia with severe CAA (Vidal et al., 1999) is characterised by de-
mentia, progressive spastic tetraparesis and cerebellar ataxia, the
onset is usually in the sixth decade (Mead et al., 2000). Neuro-
pathological features also include Alzheimer-type neurofibrillary
tangles and neuropil threads in the anteromedial temporal lobe
that may contribute of dementia (Plant et al., 1990; Revesz et al.,
2009). Familial Danish dementia (FDD), also known as here-
dopathia ophthalmo-oto-encephalica, is another condition with
severe and widespread CAA (Vidal et al., 2000). FDD is charac-
terised clinically by cataracts, deafness, progressive ataxia and
dementia.
1.11. Familial small vessel diseases causing a VaD syndrome
Several familial stroke disorders also appear to cause cognitive
impairment or dementia. These can be diagnosed in biopsy tissues
using immunohistochemical or electron microscopy methods
(Table 1). A common feature in these is subcortical SVD often
characterised by severe arteriolosclerosis in the perforating vessels
(Yamamoto et al., 2011). Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL) is the
most common form of hereditary SVDs (Chabriat et al., 2009). It is
caused by over 250 distinct mutations in the NOTCH3 gene. Recent
extensive exome analysis suggested that the frequency of distinc-
tive epidermal growth factor region cysteine altering NOTCH3
mutations appear to be 100-fold greater than simply based on
CADASIL prevalence (Rutten et al., 2016). Vascular changes
including apoptotic loss of brain vascular smooth muscle cells (Gray
et al., 2007) and vessel wall thickening (Craggs et al., 2013) likely
reduce blood flow and affect the vasodilatory response to cause
lacunar infarcts and microinfarcts in grey matter and WM
(Yamamoto et al., 2011). The extensive demyelination and axonal
damage in the underlying WM contributes to cortical atrophy
(Craggs et al., 2013) impacting on frontal lobe cognitive function.
This is consistent with the disconnection of the fronto-striatal cir-
cuits in CADASIL. Neuronal apoptosis, predominantly in neocortical
layers III and V (Gray et al., 2007) and the widespread astrocytop-
athy likely contribute to dementia in CADASIL (Y Hase et al., un-
published observations).
Cerebral autosomal recessive arteriopathy with subcortical in-
farcts and leukoencephalopathy (CARASIL) is an autosomal reces-
sive disorder characterised by extensive loss of arterial medial
smooth muscle cells (Hara et al., 2009) and mutations in the HTRA1
gene. Normotensive affected subjects also exhibit severe leu-
koencephalopathy and lacunar infarcts with or without spinal
anomalies and alopecia (Menezes Cordeiro et al., 2015). Patients
with longer time from the onset of cognitive impairment have
grearter MRI severity. In the earlier stages, the frontal WM and
external capsule are affected (Nozaki et al., 2015). Strokes lead to
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
stepwise deterioration with most subjects becoming demented in
older age. Familial cerebral SVDs involving progressive visual
impairment (Yamamoto et al., 2011) cause deterioration in cogni-
tive function. Hereditary endotheliopathy with retinopathy, ne-
phropathy and stroke (HERNS), cerebroretinal vasculopathy (CRV)
and hereditary vascular retinopathy (HVR) were reported inde-
pendently but represent different phenotypes in the same disease
spectrum (Jen et al., 1997; Ophoff et al., 2001; Terwindt et al., 1998).
These now described as autosomal dominant retinal vasculopathy
with cerebral leukodystrophy lead to early death and cause de-
mentia. Retinal microvessels undergo severe distortions and
become tortuous predictive of the SVD type of pathology with
multilaminated vascular basement membranes in the brain (Jen
et al., 1997).
Some rarer and less characterised hereditary SVDs (Table 1)
including the recently characterised collagen IV (COL4) disorders
have come to light (Siitonen et al., 2017; Verdura et al., 2016). These
are associated with clinical SVD features and different degrees of
cognitive impairment but the pathologies in these are not
described. They include conditions with abnormalities in the skin
and eye and multiple lacunar infarcts in deep WM and pons
(Pavlovic et al., 2005), retinal arteriolar tortuosity and leukoence-
phalopathy (Gould et al., 2006; Vahedi et al., 2003) and profound
WM changes upon MRI (Verreault et al., 2006).
1.12. Recent developments in clinicopathological correlation in VaD
In the past, several proposals were made to better define the
diagnostic criteria for VaD (Wiederkehr et al., 2008a, b). These have
variable specificities and sensitivities and are not interchangeable
with substantial misclassification of dementias (Alafuzoff et al.,
2012; Cosentino et al., 2004; Gold et al., 2002; Pantoni et al.,
2006; Pohjasvaara et al., 2000). It is quite clear that robust neuro-
pathological diagnostic criteria for the confirmation of VaD are
lacking. While neuroimaging and clinicopathological studies have
indicated that the threshold for VaD depends on the extent of ce-
rebral damage, a combination of factors including origin, timing,
volume, location and number of lesions contribute to the devel-
opment of dementia.
The Oxford Project to Investigate Memory and Ageing (OPTIMA)
study has recently developed a simple, novel, image-matching
scoring system (Smallwood et al., 2012) to relate the extent of
SVD with cognitive function in a study of 70 cases with insufficient
pathology for the diagnosis of AD. Severity of SVD pathology was
inversely related to cognitive scores and 43% of the cases with high
SVD scores were designated to be demented. To better define
clinicopathological correlation in subtypes of VaD including SVD, a
staging system related to the natural history of cerebrovascular
pathology and an algorithm for the neuropathological quantifica-
tion of the CVD burden in dementia have been proposed
(Deramecourt et al., 2012). The staging system (I-VI) needs further
evaluation against cognitive function scores to determine whether
this system can be used in large-scale studies to understand clini-
copathological correlations (Kalaria, 2016; Kalaria et al., 2004).
Clearly, assessing the neuropathological substrates of VaD in-
volves systematic assessment of parenchymal lesions, including
microinfarcts and haemorrhages and the vascular abnormalities
that may have caused them to relate to progression of impairment
(Deramecourt et al., 2012; Kalaria et al., 2004; Mirra, 1997;
Smallwood et al., 2012; Strozyk et al., 2010). In addition, systemic
factors (e.g., hypotension, hypoglycemia) may cause brain or
neuronal lesions in the absence of severe vascular disease and need
to be taken into account when attributing causes to VaD. In addi-
tion, parenchymal abnormalities of neurodegenerative type may be
present that are not obviously associated with either vascular
235
disease or systemic factors i.e. Alzheimer type or hippocampal
lesions.
In an effort to resolve some of the inherent issues, the neuro-
pathology VCI criteria (Table 2) were developed that are repro-
ducible and clinically predictive (Skrobot et al., 2016). The analyses
involved blinded assessment of brain tissue from individuals
(55e100 years) without significant neurodegenerative disease who
had had formal cognitive assessments within 12 months of death.
Fourteen different vessel and parenchymal pathologies were
assessed in 13 brain regions (Kalaria, 2016). Almost perfect agree-
ment was found when the agreed criteria were used for assessment
of large infarcts, lacunar infarcts, microhaemorrhage, larger hae-
morrhage, fibrinoid necrosis, microaneurysms, perivascular space
dilation, perivascular haemosiderin leakage, myelin loss and lep-
tomeningeal, cortical and capillary cerebral amyloid angiopathy
(Fig. 4). Of these pathologies the best predictors of cognitive
impairment by multiple regression analysis were seven including
lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space
dilation, myelin loss and leptomeningeal CAA (Skrobot et al., 2016).
However, as with the Canadian Stroke Network-NINDS Harmoni-
zation guidelines (Hachinski et al., 2006b) and the AHA statement
procedures (Gorelick et al., 2011) wider use and testing of these in
different cohorts as diverse as practicable is much needed.
2. Summary
Defining the neuropathological substrates of VaD relies on
adequate clinical information and rigorous pathological examina-
tion. VaD resulting from severe VCI or vascular cognitive disorder or
from delayed impairment after stroke appears to result from the
accumulation of several lesions including cerebral atrophy. Diffuse
WM changes involving periventricular and deeper regions are
frequent in VaD. While robust neuropathological criteria for VaD
are still wanting, recent neuropathology guidelines for VCI suggest
cortical infarcts, lacunes and microinfarcts most represented by
SVD correlate with cognitive impairment. Further definitions of the
neuropathological and neurochemical correlates of VaD and
investigation of genetic models would be valuable for exploring the
pathogenesis as well as management of SVD as the most common
feature of VaD.
Funding sources
Over the past 18 years various aspects of my work has been
supported by the RCUK Newcastle Centre for Brain Ageing and
Vitality (G0700718), Medical Research Council (G9817621,
G0500247, G0400074, G0900652, G1100540), Alzheimer’s Research
UK (PG2013-022), the Dunhill Medical Trust, UK (R2777/0213) and
the Newcastle National Institute for Health Research Biomedical
Research Centre in Ageing and Age Related Diseases, Newcastle
upon Tyne Hospitals National Health Service Foundation Trust.
Conflicts of interest
I declare no competing interests.
Acknowledgments
I am indebted to Dr Yumi Yamamoto (Osaka) for constructing
and providing images used in Figs. 3 and 4. I am thankful to Arthur
Oakley and Janet Slade as loyal members of the Neurovascular
Research Group for providing continued technical support.
236 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239

References Cambridge.
CFAS, 2001. Pathological correlates of late-onset dementia in a multicentre,
community-based population in England and wales. Neuropathology group of
Adams Jr., H.P., Bendixen, B.H., Kappelle, L.J., Biller, J., Love, B.B., Gordon, D.L.,
the medical research Council cognitive function and ageing study (MRC CFAS).
Marsh 3rd, E.E., 1993. Classification of subtype of acute ischemic stroke. Defi-
Lancet 357, 169e175.
nitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute
Chabriat, H., Joutel, A., Dichgans, M., Tournier-Lasserve, E., Bousser, M.G., 2009.
Stroke Treatment. Stroke 24, 35e41.
CADASIL. Lancet Neurol. 8, 643e653.
Akatsu, H., Takahashi, M., Matsukawa, N., Ishikawa, Y., Kondo, N., Sato, T.,
Charidimou, A., Gang, Q., Werring, D.J., 2012. Sporadic cerebral amyloid angiopathy
Nakazawa, H., Yamada, T., Okada, H., Yamamoto, T., Kosaka, K., 2002. Subtype
revisited: recent insights into pathophysiology and clinical spectrum. J Neurol
analysis of neuropathologically diagnosed patients in a Japanese geriatric
Neurosurg Psychiatry 83, 124e137.
hospital. J. Neurol. Sci. 196, 63e69.
Cohen, D.L., Hedera, P., Premkumar, D.R., Friedland, R.P., Kalaria, R.N., 1997. Amyloid-
Akinyemi, R.O., Allan, L., Oakley, A., Kalaria, R., 2017. Hippocampal neurodegener-
beta protein angiopathies masquerading as Alzheimer's disease? Ann. N. Y.
ative pathology in post-stroke dementia compared to other dementias and
Acad. Sci. 826, 390e395.
ageing controls. Front. Neurosci. 11, 717.
Corraini, P., Henderson, V.W., Ording, A.G., Pedersen, L., Horvath-Puho, E.,
Alafuzoff, I., Gelpi, E., Al-Sarraj, S., Arzberger, T., Attems, J., Bodi, I., Bogdanovic, N.,
Sorensen, H.T., 2017. Long-term risk of dementia among survivors of ischemic
Budka, H., Bugiani, O., Englund, E., Ferrer, I., Gentleman, S., Giaccone, G.,
or hemorrhagic stroke. Stroke 48, 180e186.
Graeber, M.B., Hortobagyi, T., Hoftberger, R., Ironside, J.W., Jellinger, K.,
Cosentino, S.A., Jefferson, A.L., Carey, M., Price, C.C., Davis-Garrett, K., Swenson, R.,
Kavantzas, N., King, A., Korkolopoulou, P., Kovacs, G.G., Meyronet, D.,
Libon, D.J., 2004. The clinical diagnosis of vascular dementia: a comparison
Monoranu, C., Parchi, P., Patsouris, E., Roggendorf, W., Rozemuller, A.,
among four classification systems and a proposal for a new paradigm. Clin.
Seilhean, D., Streichenberger, N., Thal, D.R., Wharton, S.B., Kretzschmar, H.,
Neuropsychol. 18, 6e21.
2012. The need to unify neuropathological assessments of vascular alterations
Craggs, L.J., Yamamoto, Y., Ihara, M., Fenwick, R., Burke, M., Oakley, A.E., Roeber, S.,
in the ageing brain: multicentre survey by the BrainNet Europe consortium.
Duering, M., Kretzschmar, H., Kalaria, R.N., 2013. White matter pathology and
Exp. Gerontol. 47, 825e833.
disconnection in the frontal lobe in CADASIL. Neuropathol Appl Neurobiol.
Allan, L.M., Rowan, E.N., Firbank, M.J., Thomas, A.J., Parry, S.W., Polvikoski, T.M.,
Deramecourt, V., Slade, J.Y., Oakley, A.E., Perry, R.H., Ince, P.G., Maurage, C.A.,
O'Brien, J.T., Kalaria, R.N., 2012. Long term incidence of dementia, predictors of
Kalaria, R.N., 2012. Staging and natural history of cerebrovascular pathology in
mortality and pathological diagnosis in older stroke survivors. Brain 134,
dementia. Neurology 78, 1043e1050.
3716e3727.
Desmond, D.W., 2004. The neuropsychology of vascular cognitive impairment: is
Altaf, N., Daniels, L., Morgan, P.S., Lowe, J., Gladman, J., MacSweeney, S.T., Moody, A.,
there a specific cognitive deficit? J. Neurol. Sci. 226, 3e7.
Auer, D.P., 2006. Cerebral white matter hyperintense lesions are associated with
Duering, M., Csanadi, E., Gesierich, B., Jouvent, E., Herve, D., Seiler, S., Belaroussi, B.,
unstable carotid plaques. Eur. J. Vasc. Endovasc. Surg. 31, 8e13.
Ropele, S., Schmidt, R., Chabriat, H., Dichgans, M., 2013. Incident lacunes pref-
Alzamora, M.T., Sorribes, M., Heras, A., Vila, N., Vicheto, M., Fores, R., Sanchez-
erentially localize to the edge of white matter hyperintensities: insights into the
Ojanguren, J., Sancho, A., Group, I.S., Pera, G., 2008. Ischemic stroke incidence in
pathophysiology of cerebral small vessel disease. Brain 136, 2717e2726.
Santa Coloma de Gramenet (ISISCOG), Spain. A community-based study. BMC
Ellis, R.J., Olichney, J.M., Thal, L.J., Mirra, S.S., Morris, J.C., Beekly, D., Heyman, A.,
Neurol. 8, 5.
1996. Cerebral amyloid angiopathy in the brains of patients with Alzheimer's
Amarenco, P., Bogousslavsky, J., Caplan, L.R., Donnan, G.A., Hennerici, M.G., 2009.
disease: the CERAD experience, Part XV. Neurology 46, 1592e1596.
Classification of stroke subtypes. Cerebrovasc. Dis. 27, 493e501.
Englund, E., 1998. Neuropathology of white matter changes in Alzheimer's disease
Arvanitakis, Z., Leurgans, S.E., Barnes, L.L., Bennett, D.A., Schneider, J.A., 2011a.
and vascular dementia. Dement. Geriatr. Cognit. Disord. 9 (Suppl. l), 6e12, 1.
Microinfarct pathology, dementia, and cognitive systems. Stroke 42, 722e727.
Esiri, M.M., Wilcock, G.K., Morris, J.H., 1997. Neuropathological assessment of the
Arvanitakis, Z., Leurgans, S.E., Wang, Z., Wilson, R.S., Bennett, D.A., Schneider, J.A.,
lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 63,
2011b. Cerebral amyloid angiopathy pathology and cognitive domains in older
749e753.
persons. Ann. Neurol. 69, 320e327.
Fazekas, F., Kleinert, R., Roob, G., Kleinert, G., Kapeller, P., Schmidt, R., Hartung, H.P.,
Association, A.P., 2013. Diagnostic and statistical manual of mental disorders APA.
1999. Histopathologic analysis of foci of signal loss on gradient-echo T2*-
United States.
weighted MR images in patients with spontaneous intracerebral hemorrhage:
Attems, J., Jellinger, K., Thal, D.R., Van Nostrand, W., 2011. Review: sporadic cerebral
evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 20,
amyloid angiopathy. Neuropathol. Appl. Neurobiol. 37, 75e93.
637e642.
Bailey, E.L., Smith, C., Sudlow, C.L., Wardlaw, J.M., 2012. Pathology of lacunar
Fernando, M.S., Simpson, J.E., Matthews, F., Brayne, C., Lewis, C.E., Barber, R.,
ischemic stroke in humansea systematic review. Brain Pathol. 22, 583e591.
Kalaria, R.N., Forster, G., Esteves, F., Wharton, S.B., Shaw, P.J., O'Brien, J.T.,
Ballard, C., McKeith, I., O'Brien, J., Kalaria, R., Jaros, E., Ince, P., Perry, R., 2000.
Ince, P.G., 2006. White matter lesions in an unselected cohort of the elderly:
Neuropathological substrates of dementia and depression in vascular dementia,
molecular pathology suggests origin from chronic hypoperfusion injury. Stroke
with a particular focus on cases with small infarct volumes. Dement. Geriatr.
37, 1391e1398.
Cognit. Disord. 11, 59e65.
Ferro, J.M., Massaro, A.R., Mas, J.L., 2010. Aetiological diagnosis of ischaemic stroke
Barker, R., Ashby, E.L., Wellington, D., Barrow, V.M., Palmer, J.C., Kehoe, P.G.,
in young adults. Lancet Neurol. 9, 1085e1096.
Esiri, M.M., Love, S., 2014. Pathophysiology of white matter perfusion in Alz-
Filosto, M., Tomelleri, G., Tonin, P., Scarpelli, M., Vattemi, G., Rizzuto, N., Padovani, A.,
heimer's disease and vascular dementia. Brain 137, 1524e1532.
Simonati, A., 2007. Neuropathology of mitochondrial diseases. Biosci. Rep. 27,
Barker, W.W., Luis, C.A., Kashuba, A., Luis, M., Harwood, D.G., Loewenstein, D.,
23e30.
Waters, C., Jimison, P., Shepherd, E., Sevush, S., Graff-Radford, N., Newland, D.,
Fisher, C.M., 1982. Lacunar strokes and infarcts: a review. Neurology 32, 871e876.
Todd, M., Miller, B., Gold, M., Heilman, K., Doty, L., Goodman, I., Robinson, B.,
Freitas, S., Simoes, M.R., Alves, L., Vicente, M., Santana, I., 2012. Montreal Cognitive
Pearl, G., Dickson, D., Duara, R., 2002. Relative frequencies of Alzheimer disease,
Assessment (MoCA): validation study for vascular dementia. J. Int. Neuro-
Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis
psychol. Soc. 18, 1031e1040.
in the State of Florida Brain Bank. Alzheimer Dis. Assoc. Disord. 16, 203e212.
Giannakopoulos, P., Gold, G., Kovari, E., von Gunten, A., Imhof, A., Bouras, C.,
Bejot, Y., Aboa-Eboule, C., Durier, J., Rouaud, O., Jacquin, A., Ponavoy, E., Richard, D.,
Hof, P.R., 2007. Assessing the cognitive impact of Alzheimer disease pathology
Moreau, T., Giroud, M., 2011. Prevalence of early dementia after first-ever
and vascular burden in the aging brain: the Geneva experience. Acta Neuro-
stroke: a 24-year population-based study. Stroke 42, 607e612.
pathol. 113, 1e12.
Bejot, Y., Caillier, M., Ben Salem, D., Couvreur, G., Rouaud, O., Osseby, G.V., Durier, J.,
Giwa, M.O., Williams, J., Elderfield, K., Jiwa, N.S., Bridges, L.R., Kalaria, R.N.,
Marie, C., Moreau, T., Giroud, M., 2008. Ischaemic stroke subtypes and associ-
Markus, H.S., Esiri, M.M., Hainsworth, A.H., 2012. Neuropathologic evidence of
ated risk factors: a French population based study. J Neurol Neurosurg Psy-
endothelial changes in cerebral small vessel disease. Neurology 78, 167e174.
chiatry 79, 1344e1348.
Gold, G., Bouras, C., Canuto, A., Bergallo, M.F., Herrmann, F.R., Hof, P.R., Mayor, P.A.,
Bogiatzi, C., Wannarong, T., McLeod, A.I., Heisel, M., Hackam, D., Spence, J.D., 2014.
Michel, J.P., Giannakopoulos, P., 2002. Clinicopathological validation study of
SPARKLE (Subtypes of Ischaemic Stroke Classification System), incorporating
four sets of clinical criteria for vascular dementia. Am J Psychiatry 159, 82e87.
measurement of carotid plaque burden: a new validated tool for the classifi-
Goodman, R.A., Lochner, K.A., Thambisetty, M., Wingo, T.S., Posner, S.F., Ling, S.M.,
cation of ischemic stroke subtypes. Neuroepidemiology 42, 243e251.
2017. Prevalence of dementia subtypes in United States Medicare fee-for-service
Brown, W.R., Moody, D.M., Challa, V.R., Thore, C.R., Anstrom, J.A., 2002a. Apoptosis
beneficiaries, 2011-2013. Alzheimers Dement 13, 28e37.
in leukoaraiosis lesions. J. Neurol. Sci. 203-204, 169e171.
Gorelick, P.B., Scuteri, A., Black, S.E., Decarli, C., Greenberg, S.M., Iadecola, C.,
Brown, W.R., Moody, D.M., Challa, V.R., Thore, C.R., Anstrom, J.A., 2002b. Venous
Launer, L.J., Laurent, S., Lopez, O.L., Nyenhuis, D., Petersen, R.C., Schneider, J.A.,
collagenosis and arteriolar tortuosity in leukoaraiosis. J. Neurol. Sci. 203-204,
Tzourio, C., Arnett, D.K., Bennett, D.A., Chui, H.C., Higashida, R.T., Lindquist, R.,
159e163.
Nilsson, P.M., Roman, G.C., Sellke, F.W., Seshadri, S., American Heart Association
Brown, W.R., Thore, C.R., 2011. Review: cerebral microvascular pathology in ageing
Stroke Council, C. o. E., Prevention, C.o.C.N.C.o.C.R., Intervention, Council on
and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56e74.
Cardiovascular, S., Anesthesia, 2011. Vascular contributions to cognitive
Brundel, M., de Bresser, J., van Dillen, J.J., Kappelle, L.J., Biessels, G.J., 2012. Cerebral
impairment and dementia: a statement for healthcare professionals from the
microinfarcts: a systematic review of neuropathological studies. J. Cerebr. Blood
american heart association/american stroke association. Stroke 42, 2672e2713.
Flow Metabol. 32, 425e436.
Gould, D.B., Phalan, F.C., van Mil, S.E., Sundberg, J.P., Vahedi, K., Massin, P.,
Cadavid, D., Mena, H., Koeller, K., Frommelt, R.A., 2000. Cerebral beta amyloid
Bousser, M.G., Heutink, P., Miner, J.H., Tournier-Lasserve, E., John, S.W., 2006.
angiopathy is a risk factor for cerebral ischemic infarction. A case control study
Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N. Engl. J. Med.
in human brain biopsies. J. Neuropathol. Exp. Neurol. 59, 768e773.
354, 1489e1496.
Caplan, L.R., 2008. Uncommon causes of stroke Cambridge University Press,
Gray, F., Polivka, M., Viswanathan, A., Baudrimont, M., Bousser, M.G., Chabriat, H.,
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
2007. Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical
infarcts and leukoencephalopathy. J. Neuropathol. Exp. Neurol. 66, 597e607.
Greenberg, S.M., Nandigam, R.N., Delgado, P., Betensky, R.A., Rosand, J.,
Viswanathan, A., Frosch, M.P., Smith, E.E., 2009. Microbleeds versus macro-
bleeds: evidence for distinct entities. Stroke 40, 2382e2386.
Grinberg, L.T., Thal, D.R., 2010. Vascular pathology in the aged human brain. Acta
Neuropathol. 119, 277e290.
Gulli, G., Rutten-Jacobs, L.C., Kalra, L., Rudd, A.G., Wolfe, C.D., Markus, H.S., 2016.
Differences in the distribution of stroke subtypes in a UK black stroke popu-
lation - final results from the South London Ethnicity and Stroke Study. BMC
Med. 14, 77.
Haan, J., Lanser, J.B., Zijderveld, I., van der Does, I.G., Roos, R.A., 1990. Dementia in
hereditary cerebral hemorrhage with amyloidosis-Dutch type. Arch. Neurol. 47,
965e967.
Hachinski, V., Iadecola, C., Petersen, R.C., Breteler, M.M., Nyenhuis, D.L., Black, S.E.,
Powers, W.J., DeCarli, C., Merino, J.G., Kalaria, R.N., Vinters, H.V., Holtzman, D.M.,
Rosenberg, G.A., Dichgans, M., Marler, J.R., Leblanc, G.G., 2006a. National
Institute of neurological disorders and stroke-canadian stroke Network vascular
cognitive impairment harmonization standards. Stroke 37, 2220e2241.
Hachinski, V., Iadecola, C., Petersen, R.C., Breteler, M.M., Nyenhuis, D.L., Black, S.E.,
Powers, W.J., DeCarli, C., Merino, J.G., Kalaria, R.N., Vinters, H.V., Holtzman, D.M.,
Rosenberg, G.A., Wallin, A., Dichgans, M., Marler, J.R., Leblanc, G.G., 2006b.
National Institute of neurological disorders and stroke-canadian stroke
Network vascular cognitive impairment harmonization standards. Stroke 37,
2220e2241.
Haglund, M., Passant, U., Sjobeck, M., Ghebremedhin, E., Englund, E., 2006. Cerebral
amyloid angiopathy and cortical microinfarcts as putative substrates of vascular
dementia. Int J Geriatr Psychiatry 21, 681e687.
Hajat, C., Heuschmann, P.U., Coshall, C., Padayachee, S., Chambers, J., Rudd, A.G.,
Wolfe, C.D., 2011. Incidence of aetiological subtypes of stroke in a multi-ethnic
population based study: the South London Stroke Register. J Neurol Neurosurg
Psychiatry 82, 527e533.
Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H.,
Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., Tamura, M., Shimoe, Y.,
Hirayama, M., Arisato, T., Yanagawa, S., Tanaka, A., Nakano, I., Ikeda, S.,
Yoshida, Y., Yamamoto, T., Ikeuchi, T., Kuwano, R., Nishizawa, M., Tsuji, S.,
Onodera, O., 2009. Association of HTRA1 mutations and familial ischemic ce-
rebral small-vessel disease. N. Engl. J. Med. 360, 1729e1739.
Hassan, A., Hunt, B.J., O'Sullivan, M., Parmar, K., Bamford, J.M., Briley, D.,
Brown, M.M., Thomas, D.J., Markus, H.S., 2003. Markers of endothelial
dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 126,
424e432.
Highley, J.R., Gebril, O.H., Simpson, J.E., Wharton, S.B., Kirby, J., O'Brien, J.T.,
Barber, R., Kalaria, R.N., Brayne, C., Lewis, C.E., Shaw, P.J., Ince, P., 2014. Axonal
preservation in deep subcortical white matter lesions in the ageing brain.
Ageing Soc. 2, 118e119.
Ho, K.L., Garcia, J.H., 2000. Neuropathology of the small blood vessels in selected
disease of the cerebral white matter. In: Pantoni, L., Inzitari, D., Wallin, A. (Eds.),
The Matter of White Matter. Academic Pharmaceutical Productions, Utrecht,
The Netherlands, pp. 247e273.
Ihara, M., Polvikoski, T.M., Hall, R., Slade, J.Y., Perry, R.H., Oakley, A.E., Englund, E.,
O'Brien, J.T., Ince, P.G., Kalaria, R.N., 2010. Quantification of myelin loss in frontal
lobe white matter in vascular dementia, Alzheimer's disease, and dementia
with Lewy bodies. Acta Neuropathol. 119, 579e589.
Ihle-Hansen, H., Thommessen, B., Wyller, T.B., Engedal, K., Fure, B., 2012. Risk factors
for and incidence of subtypes of ischemic stroke. Funct. Neurol. 27, 35e40.
Ince, P.G., Minett, T., Forster, G., Brayne, C., Wharton, S.B., Medical Research Council
Cognitive, F., Ageing Neuropathology, S., 2017. Microinfarcts in an older
population-representative brain donor cohort (MRC CFAS): prevalence, relation
to dementia and mobility, and implications for the evaluation of cerebral small
vessel disease. Neuropathol. Appl. Neurobiol. 43, 409e418.
Janaway, B.M., Simpson, J.E., Hoggard, N., Highley, J.R., Forster, G., Drew, D.,
Gebril, O.H., Matthews, F.E., Brayne, C., Wharton, S.B., Ince, P.G.,
Function, M.R.C.C., Ageing Neuropathology, S., 2014. Brain haemosiderin in
older people: pathological evidence for an ischaemic origin of magnetic reso-
nance imaging (MRI) microbleeds. Neuropathol. Appl. Neurobiol. 40, 258e269.
Jellinger, K.A., 2008. The pathology of "vascular dementia": a critical update.
J Alzheimers Dis 14, 107e123.
Jen, J., Cohen, A.H., Yue, Q., Stout, J.T., Vinters, H.V., Nelson, S., Baloh, R.W., 1997.
Hereditary endotheliopathy with retinopathy, nephropathy, and stroke
(HERNS). Neurology 49, 1322e1330.
Kalaria, R.N., 2012. Cerebrovascular disease and mechanisms of cognitive impair-
ment: evidence from clinicopathological studies in humans. Stroke 43,
2526e2534.
Kalaria, R.N., 2016. Neuropathological diagnosis of vascular cognitive impairment
and vascular dementia with implications for Alzheimer's disease. Acta Neuro-
pathol. 131, 659e685.
Kalaria, R.N., Ferrer, I., Love, S., 2015. Vascular disease, hypoxia and related condi-
tions. In: Love, S., Perry, A., Ironside, J., Budka, H. (Eds.), Greenfield's Neuropa-
thology. CRC Press, London, pp. 59e209.
Kalaria, R.N., Kenny, R.A., Ballard, C.G., Perry, R., Ince, P., Polvikoski, T., 2004. Towards
defining the neuropathological substrates of vascular dementia. J. Neurol. Sci.
226, 75e80.
Kiuru, S., Salonen, O., Haltia, M., 1999. Gelsolin-related spinal and cerebral amyloid
angiopathy. Ann. Neurol. 45, 305e311.
237
Knopman, D.S., Parisi, J.E., Boeve, B.F., Cha, R.H., Apaydin, H., Salviati, A., Edland, S.D.,
Rocca, W.A., 2003. Vascular dementia in a population-based autopsy study.
Arch. Neurol. 60, 569e575.
Kolominsky-Rabas, P.L., Weber, M., Gefeller, O., Neundoerfer, B., Heuschmann, P.U.,
2001. Epidemiology of ischemic stroke subtypes according to TOAST criteria:
incidence, recurrence, and long-term survival in ischemic stroke subtypes: a
population-based study. Stroke 32, 2735e2740.
Kovari, E., Gold, G., Herrmann, F.R., Canuto, A., Hof, P.R., Bouras, C.,
Giannakopoulos, P., 2007. Cortical microinfarcts and demyelination affect
cognition in cases at high risk for dementia. Neurology 68, 927e931.
Kovari, E., Gold, G., Herrmann, F.R., Canuto, A., Hof, P.R., Michel, J.P., Bouras, C.,
Giannakopoulos, P., 2004. Cortical microinfarcts and demyelination signifi-
cantly affect cognition in brain aging. Stroke 35, 410e414.
Kovari, E., Herrmann, F.R., Gold, G., Hof, P.R., Charidimou, A., 2017. Association of
cortical microinfarcts and cerebral small vessel pathology in the ageing brain.
Neuropathol. Appl. Neurobiol. 43, 505e513.
Lammie, G.A., Brannan, F., Slattery, J., Warlow, C., 1997. Nonhypertensive cerebral
small-vessel disease. An autopsy study. Stroke 28, 2222e2229.
Launer, L.J., Hughes, T.M., White, L.R., 2011. Microinfarcts, brain atrophy, and
cognitive function: the Honolulu Asia aging study autopsy study. Ann. Neurol.
70, 774e780.
Levy, E., Lopez-Otin, C., Ghiso, J., Geltner, D., Frangione, B., 1989. Stroke in Icelandic
patients with hereditary amyloid angiopathy is related to a mutation in the
cystatin C gene, an inhibitor of cysteine proteases. J. Exp. Med. 169, 1771e1778.
Leys, D., Henon, H., Mackowiak-Cordoliani, M.A., Pasquier, F., 2005. Poststroke de-
mentia. Lancet Neurol. 4, 752e759.
Li, L., Yiin, G.S., Geraghty, O.C., Schulz, U.G., Kuker, W., Mehta, Z., Rothwell, P.M.,
Oxford Vascular, S., 2015. Incidence, outcome, risk factors, and long-term
prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a
population-based study. Lancet Neurol. 14, 903e913.
Love, S., Chalmers, K., Ince, P., Esiri, M., Attems, J., Kalaria, R., Jellinger, K.,
Yamada, M., McCarron, M., Minett, T., Matthews, F., Greenberg, S., Mann, D.,
Kehoe, P.G., 2015. Erratum: development, appraisal, validation and imple-
mentation of a consensus protocol for the assessment of cerebral amyloid
angiopathy in post-mortem brain tissue. Am J Neurodegener Dis 4, 49.
Marnane, M., Duggan, C.A., Sheehan, O.C., Merwick, A., Hannon, N., Curtin, D.,
Harris, D., Williams, E.B., Horgan, G., Kyne, L., McCormack, P.M., Duggan, J.,
Moore, A., Crispino-O'Connell, G., Kelly, P.J., 2010. Stroke subtype classification
to mechanism-specific and undetermined categories by TOAST, A-S-C-O, and
causative classification system: direct comparison in the North Dublin popu-
lation stroke study. Stroke 41, 1579e1586.
McArdle, P.F., Kittner, S.J., Ay, H., Brown Jr., R.D., Meschia, J.F., Rundek, T., Wasser-
theil-Smoller, S., Woo, D., Andsberg, G., Biffi, A., Brenner, D.A., Cole, J.W.,
Corriveau, R., de Bakker, P.I., Delavaran, H., Dichgans, M., Grewal, R.P., Gwinn, K.,
Huq, M., Jern, C., Jimenez-Conde, J., Jood, K., Kaplan, R.C., Katschnig, P.,
Katsnelson, M., Labovitz, D.L., Lemmens, R., Li, L., Lindgren, A., Markus, H.S.,
Peddareddygari, L.R., Pedersen, A., Pera, J., Redfors, P., Roquer, J., Rosand, J.,
Rost, N.S., Rothwell, P.M., Sacco, R.L., Sharma, P., Slowik, A., Sudlow, C., Thijs, V.,
Tiedt, S., Valenti, R., Worrall, B.B., Study, N.S., 2014. Agreement between TOAST
and CCS ischemic stroke classification: the NINDS SiGN study. Neurology 83,
1653e1660.
Mead, S., James-Galton, M., Revesz, T., Doshi, R.B., Harwood, G., Pan, E.L., Ghiso, J.,
Frangione, B., Plant, G., 2000. Familial British dementia with amyloid angiop-
athy: early clinical, neuropsychological and imaging findings. Brain 123 (Pt 5),
975e991.
Menezes Cordeiro, I., Nzwalo, H., Sa, F., Ferreira, R.B., Alonso, I., Afonso, L., Basilio, C.,
2015. Shifting the CARASIL paradigm: report of a non-Asian family and litera-
ture review. Stroke 46, 1110e1112.
Mirra, S.S., 1997. The CERAD neuropathology protocol and consensus recommen-
dations for the postmortem diagnosis of Alzheimer's disease: a commentary.
Neurobiol. Aging 18, S91eS94.
Mok, V.C., Lam, B.Y., Wong, A., Ko, H., Markus, H.S., Wong, L.K., 2017. Early-onset and
delayed-onset poststroke dementia - revisiting the mechanisms. Nat. Rev.
Neurol. 13, 148e159.
Natte, R., Maat-Schieman, M.L., Haan, J., Bornebroek, M., Roos, R.A., van Duinen, S.G.,
2001. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch
type is associated with cerebral amyloid angiopathy but is independent of
plaques and neurofibrillary tangles. Ann. Neurol. 50, 765e772.
Nozaki, H., Sekine, Y., Fukutake, T., Nishimoto, Y., Shimoe, Y., Shirata, A.,
Yanagawa, S., Hirayama, M., Tamura, M., Nishizawa, M., Onodera, O., 2015.
Characteristic features and progression of abnormalities on MRI for CARASIL.
Neurology 85, 459e463.
O'Brien, J.T., Erkinjuntti, T., Reisberg, B., Roman, G., Sawada, T., Pantoni, L.,
Bowler, J.V., Ballard, C., DeCarli, C., Gorelick, P.B., Rockwood, K., Burns, A.,
Gauthier, S., DeKosky, S.T., 2003. Vascular cognitive impairment. Lancet Neurol.
2, 89e98.
Okamoto, Y., Ihara, M., Fujita, Y., Ito, H., Takahashi, R., Tomimoto, H., 2009. Cortical
microinfarcts in Alzheimer's disease and subcortical vascular dementia. Neu-
roreport 20, 990e996.
Okamoto, Y., Yamamoto, T., Kalaria, R.N., Senzaki, H., Maki, T., Hase, Y., Kitamura, A.,
Washida, K., Yamada, M., Ito, H., Tomimoto, H., Takahashi, R., Ihara, M., 2012.
Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes
cortical microinfarcts. Acta Neuropathol. 123, 381e394.
Olichney, J.M., Hansen, L.A., Hofstetter, C.R., Grundman, M., Katzman, R., Thal, L.J.,
1995. Cerebral infarction in Alzheimer's disease is associated with severe
238 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
amyloid angiopathy and hypertension. Arch. Neurol. 52, 702e708.
Olichney, J.M., Hansen, L.A., Lee, J.H., Hofstetter, C.R., Katzman, R., Thal, L.J., 2000.
Relationship between severe amyloid angiopathy, apolipoprotein E genotype,
and vascular lesions in Alzheimer's disease. Ann. N. Y. Acad. Sci. 903, 138e143.
Ophoff, R.A., DeYoung, J., Service, S.K., Joosse, M., Caffo, N.A., Sandkuijl, L.A.,
Terwindt, G.M., Haan, J., van den Maagdenberg, A.M., Jen, J., Baloh, R.W., Barilla-
LaBarca, M.L., Saccone, N.L., Atkinson, J.P., Ferrari, M.D., Freimer, N.B.,
Frants, R.R., 2001. Hereditary vascular retinopathy, cerebroretinal vasculopathy,
and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map
to a single locus on chromosome 3p21.1-p21.3. Am. J. Hum. Genet. 69, 447e453.
Palm, F., Urbanek, C., Wolf, J., Buggle, F., Kleemann, T., Hennerici, M.G.,
Inselmann, G., Hagar, M., Safer, A., Becher, H., Grau, A.J., 2012. Etiology, risk
factors and sex differences in ischemic stroke in the Ludwigshafen Stroke Study,
a population-based stroke registry. Cerebrovasc. Dis. 33, 69e75.
Pantoni, L., 2010. Cerebral small vessel disease: from pathogenesis and clinical
characteristics to therapeutic challenges. Lancet Neurol. 9, 689e701.
Pantoni, L., Garcia, J.H., 1997. Pathogenesis of leukoaraiosis: a review. Stroke 28,
652e659.
Pantoni, L., Sarti, C., Alafuzoff, I., Jellinger, K., Munoz, D.G., Ogata, J., Palumbo, V.,
2006. Postmortem examination of vascular lesions in cognitive impairment: a
survey among neuropathological services. Stroke 37, 1005e1009.
Pavlovic, A.M., Zidverc-Trajkovic, J., Milovic, M.M., Pavlovic, D.M., Jovanovic, Z.,
Mijajlovic, M., Petrovic, M., Kostic, V.S., Sternic, N., 2005. Cerebral small vessel
disease in pseudoxanthoma elasticum: three cases. Can. J. Neurol. Sci. 32,
115e118.
Pendlebury, S.T., Rothwell, P.M., 2009. Prevalence, incidence, and factors associated
with pre-stroke and post-stroke dementia: a systematic review and meta-
analysis. Lancet Neurol. 8, 1006e1018.
Petty, G.W., Brown Jr., R.D., Whisnant, J.P., Sicks, J.D., O'Fallon, W.M., Wiebers, D.O.,
1999. Ischemic stroke subtypes: a population-based study of incidence and risk
factors. Stroke 30, 2513e2516.
Pfeifer, L.A., White, L.R., Ross, G.W., Petrovitch, H., Launer, L.J., 2002. Cerebral am-
yloid angiopathy and cognitive function: the HAAS autopsy study. Neurology
58, 1629e1634.
Plant, G.T., Revesz, T., Barnard, R.O., Harding, A.E., Gautier-Smith, P.C., 1990. Familial
cerebral amyloid angiopathy with nonneuritic amyloid plaque formation. Brain
113 (Pt 3), 721e747.
Pohjasvaara, T., Erkinjuntti, T., Vataja, R., Kaste, M., 1997. Dementia three months
after stroke. Baseline frequency and effect of different definitions of dementia in
the Helsinki Stroke Aging Memory Study (SAM) cohort. Stroke 28, 785e792.
Pohjasvaara, T., Mantyla, R., Ylikoski, R., Kaste, M., Erkinjuntti, T., 2000. Comparison
of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for
the diagnosis of vascular dementia. national institute of neurological disorders
and stroke-association internationale pour la recherche et l'Enseignement en
neurosciences. Stroke 31, 2952e2957.
Reijmer, Y.D., van Veluw, S.J., Greenberg, S.M., 2015. Ischemic brain injury in cere-
bral amyloid angiopathy. J Cereb Blood Flow Metab.
Revesz, T., Holton, J.L., Lashley, T., Plant, G., Frangione, B., Rostagno, A., Ghiso, J.,
2009. Genetics and molecular pathogenesis of sporadic and hereditary cerebral
amyloid angiopathies. Acta Neuropathol. 118, 115e130.
Roman, G.C., 2002. Vascular dementia revisited: diagnosis, pathogenesis, treatment,
and prevention. Med. Clin. 86, 477e499.
Roman, G.C., Tatemichi, T.K., Erkinjuntti, T., Cummings, J.L., Masdeu, J.C., Garcia, J.H.,
Amaducci, L., Orgogozo, J.M., Brun, A., Hofman, A., et al., 1993. Vascular de-
mentia: diagnostic criteria for research studies. Report of the NINDS-AIREN
International Workshop. Neurology 43, 250e260.
Rosenberg, G.A., 2017. Binswanger's disease: biomarkers in the inflammatory form
of vascular cognitive impairment and dementia. J Neurochem.
Rutten, J.W., Dauwerse, H.G., Gravesteijn, G., van Belzen, M.J., van der Grond, J.,
Polke, J.M., Bernal-Quiros, M., Lesnik Oberstein, S.A., 2016. Archetypal NOTCH3
mutations frequent in public exome: implications for CADASIL. Ann Clin Transl
Neurol 3, 844e853.
Sacco, R.L., Dong, C., 2014. Declining stroke incidence and improving survival in US
communities: evidence for success and future challenges. J. Am. Med. Assoc.
312, 237e238.
Sachdev, P., 1999. Vascular cognitive disorder. Int J Geriatr Psychiatry 14, 402e403.
Sachdev, P., Kalaria, R., O'Brien, J., Skoog, I., Alladi, S., Black, S.E., Blacker, D.,
Blazer, D.G., Chen, C., Chui, H., Ganguli, M., Jellinger, K., Jeste, D.V., Pasquier, F.,
Paulsen, J., Prins, N., Rockwood, K., Roman, G., Scheltens, P., Internationlal so-
ciety for vascular, B., cognitive, D., 2014. Diagnostic criteria for vascular cogni-
tive disorders: a VASCOG statement. Alzheimer Dis. Assoc. Disord. 28, 206e218.
Saposnik, G., Caplan, L.R., Gonzalez, L.A., Baird, A., Dashe, J., Luraschi, A., Llinas, R.,
Lepera, S., Linfante, I., Chaves, C., Kanis, K., Sica, R.E., Rey, R.C., 2000. Differences
in stroke subtypes among natives and caucasians in Boston and Buenos Aires.
Stroke 31, 2385e2389.
Schneider, J.A., Arvanitakis, Z., Bang, W., Bennett, D.A., 2007. Mixed brain pathol-
ogies account for most dementia cases in community-dwelling older persons.
Neurology 69, 2197e2204.
Schulz, U.G., Rothwell, P.M., 2003. Differences in vascular risk factors between
etiological subtypes of ischemic stroke: importance of population-based
studies. Stroke 34, 2050e2059.
Seno, H., Ishino, H., Inagaki, T., Iijima, M., Kaku, K., Inata, T., 1999.
A neuropathological study of dementia in nursing homes over a 17-year period,
in Shimane Prefecture, Japan. Gerontology 45, 44e48.
Siitonen, M., Borjesson-Hanson, A., Poyhonen, M., Ora, A., Pasanen, P., Bras, J.,
Kern, S., Kern, J., Andersen, O., Stanescu, H., Kleta, R., Baumann, M., Kalaria, R.,
Kalimo, H., Singleton, A., Hardy, J., Viitanen, M., Myllykangas, L., Guerreiro, R., 1
May 2017. Multi-infarct dementia of Swedish type is caused by a 3'UTR muta-
tion of COL4A1. Brain 140, e29.
Simpson, J.E., Fernando, M.S., Clark, L., Ince, P.G., Matthews, F., Forster, G.,
O'Brien, J.T., Barber, R., Kalaria, R.N., Brayne, C., Shaw, P.J., Lewis, C.E.,
Wharton, S.B., Function, M.R.C.C., Ageing Neuropathology Study, G., 2007. White
matter lesions in an unselected cohort of the elderly: astrocytic, microglial and
oligodendrocyte precursor cell responses. Neuropathol. Appl. Neurobiol. 33,
410e419.
Simpson, J.E., Hosny, O., Wharton, S.B., Heath, P.R., Holden, H., Fernando, M.S.,
Matthews, F., Forster, G., O'Brien, J.T., Barber, R., Kalaria, R.N., Brayne, C.,
Shaw, P.J., Lewis, C.E., Ince, P.G., 2009. Microarray RNA expression analysis of
cerebral white matter lesions reveals changes in multiple functional pathways.
Stroke 40, 369e375.
Skrobot, O.A., Attems, J., Esiri, M., Hortobagyi, T., Ironside, J.W., Kalaria, R.N., King, A.,
Lammie, G.A., Mann, D., Neal, J., Ben-Shlomo, Y., Kehoe, P.G., Love, S., 2016.
Vascular cognitive impairment neuropathology guidelines (VCING): the
contribution of cerebrovascular pathology to cognitive impairment. Brain 139,
2957e2969.
Skrobot, O.A., Black, S.E., Chen, C., DeCarli, C., Erkinjuntti, T., Ford, G.A., Kalaria, R.N.,
O'Brien, J., Pantoni, L., Pasquier, F., Roman, G.C., Wallin, A., Sachdev, P., Skoog, I.,
group, V., Ben-Shlomo, Y., Passmore, A.P., Love, S., Kehoe, P.G., 2017a. Progress
toward standardized diagnosis of vascular cognitive impairment: guidelines
from the vascular impairment of cognition classification consensus study.
Alzheimers Dement.
Skrobot, O.A., O'Brien, J., Black, S., Chen, C., DeCarli, C., Erkinjuntti, T., Ford, G.A.,
Kalaria, R.N., Pantoni, L., Pasquier, F., Roman, G.C., Wallin, A., Sachdev, P.,
Skoog, I., group, V., Ben-Shlomo, Y., Passmore, A.P., Love, S., Kehoe, P.G., 2017b.
The vascular impairment of cognition classification consensus study. Alz-
heimers Dement 13, 624e633.
Smallwood, A., Oulhaj, A., Joachim, C., Christie, S., Sloan, C., Smith, A.D., Esiri, M.,
2012. 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. Neuropathol. Appl. Neurobiol. 38,
337e343.
Sonnen, J.A., Larson, E.B., Crane, P.K., Haneuse, S., Li, G., Schellenberg, G.D., Craft, S.,
Leverenz, J.B., Montine, T.J., 2007. Pathological correlates of dementia in a
longitudinal, population-based sample of aging. Ann. Neurol. 62, 406e413.
Strozyk, D., Dickson, D.W., Lipton, R.B., Katz, M., Derby, C.A., Lee, S., Wang, C.,
Verghese, J., 2010. Contribution of vascular pathology to the clinical expression
of dementia. Neurobiol. Aging 31, 1710e1720.
Suter, O.C., Sunthorn, T., Kraftsik, R., Straubel, J., Darekar, P., Khalili, K., Miklossy, J.,
2002. Cerebral hypoperfusion generates cortical watershed microinfarcts in
Alzheimer disease. Stroke 33, 1986e1992.
Tanskanen, M., Kalaria, R.N., Notkola, I.L., Makela, M., Polvikoski, T., Myllykangas, L.,
Sulkava, R., Kalimo, H., Paetau, A., Scheltens, P., Barkhof, F., van Straaten, E.,
Erkinjuntti, T., 2013. Relationships between white matter hyperintensities, ce-
rebral amyloid angiopathy and dementia in a population-based sample of the
oldest old. Curr. Alzheimer Res. 10, 1090e1097.
Terwindt, G.M., Haan, J., Ophoff, R.A., Groenen, S.M., Storimans, C.W., Lanser, J.B.,
Roos, R.A., Bleeker-Wagemakers, E.M., Frants, R.R., Ferrari, M.D., 1998. Clinical
and genetic analysis of a large Dutch family with autosomal dominant vascular
retinopathy, migraine and Raynaud's phenomenon. Brain 121 (Pt 2), 303e316.
Thomas, T., Miners, S., Love, S., 2015. Post-mortem assessment of hypoperfusion of
cerebral cortex in Alzheimer's disease and vascular dementia. Brain 138,
1059e1069.
Tsai, C.F., Thomas, B., Sudlow, C.L., 2013. Epidemiology of stroke and its subtypes in
Chinese vs white populations: a systematic review. Neurology 81, 264e272.
Vahedi, K., Massin, P., Guichard, J.P., Miocque, S., Polivka, M., Goutieres, F., Dress, D.,
Chapon, F., Ruchoux, M.M., Riant, F., Joutel, A., Gaudric, A., Bousser, M.G.,
Tournier-Lasserve, E., 2003. Hereditary infantile hemiparesis, retinal arteriolar
tortuosity, and leukoencephalopathy. Neurology 60, 57e63.
Van der Flier, W.M., Cordonnier, C., 2012. Microbleeds in vascular dementia: clinical
aspects. Exp. Gerontol. 47, 853e857.
Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C.,
Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I.,
Rosenstingl, S., Hagel, C., Kuhlenbaumer, G., Leca-Radu, E., Goux, D., Fleming, L.,
Van Agtmael, T., Chabriat, H., Chapon, F., Tournier-Lasserve, E., 2016. Disruption
of a miR-29 binding site leading to COL4A1 upregulation causes pontine
autosomal dominant microangiopathy with leukoencephalopathy. Ann. Neurol.
80, 741e753.
Vermeer, S.E., Longstreth Jr., W.T., Koudstaal, P.J., 2007. Silent brain infarcts: a sys-
tematic review. Lancet Neurol. 6, 611e619.
Verreault, S., Joutel, A., Riant, F., Neves, G., Rui Silva, M., Maciazek, J., Tournier-
Lasserve, E., Bousser, M.G., Chabriat, H., 2006. A novel hereditary small vessel
disease of the brain. Ann. Neurol. 59, 353e357.
Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., Ghiso, J., 1999.
A stop-codon mutation in the BRI gene associated with familial British de-
mentia. Nature 399, 776e781.
Vidal, R., Revesz, T., Rostagno, A., Kim, E., Holton, J.L., Bek, T., Bojsen-Moller, M.,
Braendgaard, H., Plant, G., Ghiso, J., Frangione, B., 2000. A decamer duplication
in the 3' region of the BRI gene originates an amyloid peptide that is associated
with dementia in a Danish kindred. Proc Natl Acad Sci U S A 97, 4920e4925.
Vieira, R.T., Caixeta, L., Machado, S., Silva, A.C., Nardi, A.E., Arias-Carrion, O.,
 R.N. Kalaria / Neuropharmacology 134 (2018) 226e239
Carta, M.G., 2013. Epidemiology of early-onset dementia: a review of the
literature. Clin. Pract. Epidemiol. Ment. Health 9, 88e95.
Vinters, H.V., Ellis, W.G., Zarow, C., Zaias, B.W., Jagust, W.J., Mack, W.J., Chui, H.C.,
2000. Neuropathologic substrates of ischemic vascular dementia.
J. Neuropathol. Exp. Neurol. 59, 931e945.
Viswanathan, A., Patel, P., Rahman, R., Nandigam, R.N., Kinnecom, C., Bracoud, L.,
Rosand, J., Chabriat, H., Greenberg, S.M., Smith, E.E., 2008. Tissue microstruc-
tural changes are independently associated with cognitive impairment in ce-
rebral amyloid angiopathy. Stroke 39, 1988e1992.
Wardlaw, J.M., 2010. Blood-brain barrier and cerebral small vessel disease. J. Neurol.
Sci. 299, 66e71.
Wardlaw, J.M., Smith, C., Dichgans, M., 2013. Mechanisms of sporadic cerebral small
vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483e497.
Wattendorff, A.R., Bots, G.T., Went, L.N., Endtz, L.J., 1982. Familial cerebral amyloid
angiopathy presenting as recurrent cerebral haemorrhage. J. Neurol. Sci. 55,
121e135.
Werring, D.J., Gregoire, S.M., Cipolotti, L., 2011. Cerebral microbleeds and vascular
cognitive impairment. J. Neurol. Sci. 299, 131e135.
Westover, M.B., Bianchi, M.T., Yang, C., Schneider, J.A., Greenberg, S.M., 2013. Esti-
mating cerebral microinfarct burden from autopsy samples. Neurology 80,
1365e1369.
White, L., 2009. Brain lesions at autopsy in older Japanese-American men as related
239
to cognitive impairment and dementia in the final years of life: a summary
report from the Honolulu-Asia aging study. J Alzheimers Dis 18, 713e725.
White, L., Petrovitch, H., Hardman, J., Nelson, J., Davis, D.G., Ross, G.W., Masaki, K.,
Launer, L., Markesbery, W.R., 2002. Cerebrovascular pathology and dementia in
autopsied Honolulu-Asia Aging Study participants. Ann. N. Y. Acad. Sci. 977,
9e23.
White, L., Small, B.J., Petrovitch, H., Ross, G.W., Masaki, K., Abbott, R.D., Hardman, J.,
Davis, D., Nelson, J., Markesbery, W., 2005. Recent clinical-pathologic research
on the causes of dementia in late life: update from the Honolulu-Asia Aging
Study. J. Geriatr. Psychiatr. Neurol. 18, 224e227.
Wiederkehr, S., Simard, M., Fortin, C., van Reekum, R., 2008a. Comparability of the
clinical diagnostic criteria for vascular dementia: a critical review. Part I.
J. Neuropsychiatry Clin. Neurosci. 20, 150e161.
Wiederkehr, S., Simard, M., Fortin, C., van Reekum, R., 2008b. Validity of the clinical
diagnostic criteria for vascular dementia: a critical review. Part II. J Neuropsy-
chiatry Clin Neurosci 20, 162e177.
Yamamoto, Y., Craggs, L., Baumann, M., Kalimo, H., Kalaria, R.N., 2011. Molecular
genetics and pathology of hereditary small vessel diseases of the brain. Neu-
ropathol. Appl. Neurobiol. 37, 94e113.
Yamamoto, Y., Ihara, M., Tham, C., Low, R.W., Slade, J.Y., Moss, T., Oakley, A.E.,
Polvikoski, T., Kalaria, R.N., 2009. Neuropathological correlates of temporal pole
white matter hyperintensities in CADASIL. Stroke 40, 2004e2011.