- Email: [email protected]
Vascular neuropathology and cognitive decline
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
Available online at
www.sciencedirect.com
International meeting of the French society of neurology 2013
Vascular neuropathology and cognitive decline Neuropathologie vasculaire et de´clin cognitif V. Deramecourt Centre me´moire de ressources et de recherche, CNR maladie d’Alzheimer du sujet jeune, de´partement d’histologie, EA1046, laboratoire d’excellence DISTALZ, universite´ Lille-Nord-de-France, centre hospitalier re´gional universitaire de Lille, hoˆpital Roger-Salengro, rue Emile-Laine, 59037 Lille, France
info article
abstract
Article history:
Cerebrovascular disease is an important cause of cognitive decline and dementia. Despite
Received 27 May 2013
numerous epidemiological, clinical, neuroimaging and neuropathological studies, the link
Received in revised form
between cerebrovascular lesions and their impact on cognition and behavior is still a matter
2 July 2013
of debate. Cerebrovascular lesions are heterogeneous and most descriptive studies dis-
Accepted 9 July 2013
tinguish vessel wall modifications, perivascular space modifications, white matter changes,
Available online xxx
and infarcts as the main features of vascular dementia. However, to date there is still no consensual criteria for the neuropathological diagnosis of vascular or mixed dementia. The
Keywords:
diagnosis of these conditions still relies on both clinical and neuropathological expertise. # 2013 Published by Elsevier Masson SAS.
Arteriolosclerosis Cerebral amyloid angiopathy Micro-infarcts Lacunar infarct Mots cle´s : Arterioloscle´rose Angiopathie amyloı¨de ce´re´brale Microinfarctus Lacune
r e´ s u m e´ Les pathologies ce´re´brovasculaires sont une cause importante de de´clin cognitif et de de´mence. Malgre´ de nombreux travaux e´pide´miologiques, cliniques, neuroradiologiques et neuropathologiques, les liens entre les le´sions ce´re´brovasculaires et leurs conse´quences cognitives et comportementales sont encore de´battus. L’e´ventail le´sionnel est large depuis les modifications des parois vasculaires elles-meˆmes, les modifications des espaces pe´rivasculaires, les le´sions de substance blanche, jusqu’aux infarctus tissulaires constitue´s. En l’absence de crite`res neuropathologiques consensuels de de´mence vasculaire, ce diagnostic, comme celui de de´mence mixte, doit absolument reposer sur une expertise clinicopathologique. # 2013 Publie´ par Elsevier Masson SAS.
Cerebrovascular lesions and their causal links with the emergence of cognitive decline probably constitute one of the most complex subjects in the neuropathology of dementia (Ferrer, 2010). There are three levels of explanation for this complexity. Firstly, the cerebrovascular lesions and the underlying disease mechanisms are very heterogeneous and
range from vessel wall changes to tissue damage itself. Secondly, there is still much debate over the causal relationships that drive cerebrovascular lesions and their harmful effects on cognitive function. Lastly, there is not yet any consensus on the most relevant way of assessing and quantifying cerebrovascular lesions, which therefore prevents
E-mail address: [email protected]. 0035-3787/$ – see front matter # 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2013.07.008 Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
2
revue neurologique xxx (2013) xxx–xxx
the large-scale harmonization of clinical and pathological studies.
1.
A historical overview
The 17th century physician Thomas Willis was probably the first person to describe post-stroke cognitive impairment. In the early 20th century, the famous neuropsychiatrists and pathologists Aloı¨s Alzheimer and Otto Binswanger drew a distinction between cerebrovascular lesions and syphilitic dementia. Kraepelin considered that the most frequent cause of senile dementia was arteriosclerosis, inducing a progressive narrowing of the vessels, a reduction in cerebral blood flow and neuron loss. In 1970, Tomlinson et al. published the first large study on ‘‘arteriosclerotic dementia’’ and showed that cerebrovascular lesions constituted a major cause of cognitive decline in about a third of elderly demented patients and, indeed, the only cause in about a sixth of these patients (Tomlinson et al., 1970). Tomlinson et al.’s observations were mainly based on the presence of brain infarcts: they suggested that a volume threshold of 100 mL of infarcted tissue was associated with a high risk of dementia. Hachinski completed this viewpoint by introducing the concept of multi-infarct dementia in 1974 (Hachinski et al., 1974). However, it then became clear that lesions other than infarcts could also contribute to cognitive decline. Hence, ‘‘multi-infarct dementia’’ was replaced first by the more general concept of ‘‘vascular dementia’’ (Roman et al., 1993) and then by the term ‘‘vascular cognitive impairment’’ (Gorelick et al., 2011; O’Brien et al., 2003).
2.
Cerebrovascular lesions of interest
2.1.
Vessel wall changes
The vessel wall changes most frequently linked to vascular dementia are cerebral arteriosclerosis, cerebral arteriolosclerosis and cerebral amyloid angiopathy (CAA). The frequency and the severity of these changes increase with age.
2.1.1.
Arteriosclerosis
Arteriosclerosis affects the large and medium-sized arteries of the brain and results in thickening of the tunica intima, with the accumulation of lipids (mainly cholesterol) and proteins within the vessel wall (Fig. 1B). This process is followed by the calcification of atheromatous plaques and fibrosis of the vessel wall. Plaque rupture frequently induces local thrombosis and complication of the latter by a large infarct. Embolization of the atherogenic thrombus creates an infarct of variable size.
2.1.2.
Arteriolosclerosis/lipohyalinosis
Arteriolosclerosis affects arteries with a diameter of between 40 and 150 mm and manifests itself as concentric, hyalinised thickening of the arteriolar wall, loss of smooth muscle cells and disorganisation of the tunica media (Fig. 1C) (Pantoni, 2010). Lipohyalinosis has a fairly similar appearance, although the hyalinosis and fibrosis are asymmetrically distributed and there may be fibrinoid necrosis of the arteriolar wall.
Arteriolosclerosis and lipohyalinosis are complicated by lacunar infarcts, micro-infarcts, microbleeds and/or large haemorrhages. They appear early in the course of the disease in the arterioles of the basal ganglia and then extend to the white matter, the leptomeningeal arterioles and (in severe cases) the arterioles of the cerebellum and the brain stem (Thal et al., 2003). In general, the cortical arterioles are not affected.
2.1.3.
Cerebral amyloid angiopathy
Sporadic CAA is characterized by the deposition of Ab peptides within the vessel wall. Whereas the intraparenchymatous amyloid plaques in Alzheimer’s disease (AD) are mainly constituted of Ab-42 peptide, vascular deposits (and particularly those in the leptomeningeal vessels) are mainly constituted of Ab-40 and form concentric layers that replace the smooth muscle cells. The amyloid deposits in arterioles and small cortical arteries are constituted of a mixture of Ab40 and Ab-42, whereas those affecting the capillaries are mainly composed of Ab-42 (Thal et al., 2008). In severe forms, the vessel wall is totally remodelled and weakened, with shrinkage of the lumen and the development of microaneurysms and fibrinoid necrosis (Fig. 1D). A neuropathological examination also reveals haemorrhagic complications (microbleeds and perivascular and leptomeningeal haemosiderin deposits) and ischaemic complications (cortical micro-infarcts and myelin loss). It has been suggested that two types of sporadic CAA exist: CAA type 1 is characterized by Ab deposits in cortical capillaries (in the presence or absence of damage to the other types of vessels), whereas in CAA type 2, deposits are limited to the leptomeningeal and cortical arteries and arterioles and (more rarely) venules (Thal et al., 2002). The e4 and e2 genotypes of APOE are associated with CAA types 1 and 2, respectively. The occipital lobe is the most frequently affected area, followed by the frontal, temporal and parietal lobes. The cerebellum may be damaged in late-stage disease, whereas the basal ganglia, the white matter and the brain stem are not usually affected (Thal et al., 2008). The prevalence of CAA in autopsy cohorts varies between 20 and 40% in non-demented cases and between 50 and 60% in demented cases (Keage et al., 2009). CAA is strongly associated with increasing age. CAA is almost always present in AD cases, but only 25% of them exhibit severe forms of the disease (Ellis et al., 1996). There is no etiological link between CAA and the classical vascular risk factors, despite arterial hypertension may aggravate its hemorrhagic complications. The only known genetic risk factors of CAA are E4 and E2 genotypes of APOE gene. CAA probably represents a cause of cognitive decline by itself since the association between CAA and dementia persists after adjustment for age and the severity of associated neuritic plaques (Neuropathology group of the MRC-CFAS, 2001). Thus, CAA is to be considered as a pathophysiological process located at the crossroad between microvascular and neurodegenerative pathologies.
2.1.4.
Hereditary microangiopathies
These conditions, mostly represented by the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), are usually characterized by
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
3
Fig. 1 – Main vascular modifications associated with vascular cognitive impairment. A. Normal microscopic appearance of a deep white matter artery. The nuclei of smooth muscle cells are well seen (arrow). B. Atheroma of the circle of Willis arteries. Atheromatous plaque (asterisk) is visible within the tunica media of this artery. C. Arteriolosclerosis/ lipohyalinosis. The tunica media is thickened (arrow) with severe loss of smooth muscle cells. D. Cerebral amyloid angiopathy. The vessel wall is severely modified by the accumulation of eosinophilic material corresponding to fibrillar Ab deposits (arrow). Amyloid deposition is also present in the surrounding neuropile (asterisk). Scale bar = 100 mm for all images.
progressive dementia. This specific chapter will be developed elsewhere.
2.1.5.
Other rare microangiopathies
These conditions are likely to lead to the occlusion of brain microvessels. Some diseases have an inflammatory aetiology (e.g. necrotizing angiitis, systemic erythematosus lupus, Wegener’s granulomatosis with polyangiitis and polyarteritis nodosa). Primary angiitis of the central nervous system is a related condition. Other microvessel diseases are variously caused by toxins (vasoconstrictors and drugs), tumours (endovascular lymphoma), malformations (Moyamoya disease) and genetic factors (rare Icelandic-type amyloidosis, Finnish hereditary amyloidosis and familial British dementia with amyloid angiopathy, etc.).
2.2.
Parenchymatous lesions
2.2.1.
Infarct
Brain infarcts are areas of parenchymatous necrosis caused by impaired circulation. In post-mortem analyses, the incidence of infarct increases up to the age of 91 and then levels off. The
National Institute of Neurological Disorders and Stroke – Canadian Stroke Network recommended classifying brain infarcts by size, in order to facilitate radiological correlations (Hachinski et al., 2006). Large infarcts have a greatest dimension of over 1 cm or a volume of more than 1.5 cm3 and can be seen in conventional magnetic resonance imaging (MRI). Micro-infarcts have a greatest dimension below 0.5 cm and are not generally visible in MRI (Smith et al., 2012). These infarcts have either thrombotic or embolic aetiologies. Cortical micro-infarcts (Fig. 2B) are caused by the occlusion of cortical perforating arteries and are often related to a small vessel disease, such as progressing arteriolosclerosis or an amyloid angiopathy (Kovari et al., 2007). As the number of microinfarcts increases, the brain cortex takes on a granular appearance, with an irregular decrease in the thickness of the cortical ribbon. Granular atrophy of the cerebral cortex generally predominates at the junction between the main cerebral vascular territories. Lacunae (Fig. 2A) correspond to small foci of deep infarct that are mainly related to arteriolosclerosis of the deep perforating arteries or (more rarely) embolic aetiologies (Roman, 2002a, b). The terms ‘‘lacunar infarct’’ and ‘‘ischaemic
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
4
revue neurologique xxx (2013) xxx–xxx
Fig. 2 – Macroscopic and microscopic lesions with a vascular aetiology. A. The macroscopic appearance of a lacuna in the lentiform nucleus (arrow), with cribriform changes within the thalamus (arrow heads) and greyish discoloration of the frontal white matter, sparing the U-fibres and suggesting vascular leukoencephalopathy (asterisk). B. A cortical microinfarct (HE staining), with boundaries indicated by arrows. C. ‘‘e´tat crible´’’ (HE staining) of the thalamus under the microscope, combining a micro-infarct (arrow) and enlargement of the perivascular spaces on the left side of the image. D. The microscopic appearance of vascular leukoencephalopathy, with myelin loss and a decrease in the oligodendroglial density (Luxol Fast Blue staining). E. The microscopic appearance (HE staining) of lipohyalinosis, with concentric thickening of the arteriolar wall and loss of the tunica media’s smooth muscle cells (arrow). The surrounding white matter is pigmented by haemosiderin (HE staining). Scale bar = 100 mm for all images.
lacuna’’ are sometimes used to distinguish this condition from the state in which the perivascular spaces are widened (Hauw et al., 2008). The effect of infarcts on cognitive status has been evaluated in several clinicopathological cohorts such as the Honolulu-Asia aging study, the MRC-CFAS study in the UK, and the Religious Order Study (ROS) in Chicago (Smith et al., 2012). Lacunar infarcts are probably less associated with cognitive decline than micro-infarcts (White, 2009). Microinfarcts are common, affecting almost one-third of all subjects from the ROS cohort, and present in one-third of those with dementia and one-quarter of those without (Arvanitakis et al., 2011). In this study, micro-infarcts, especially multiple cortical infarcts, independently increased odds of dementia even after accounting for macro infarcts and level of AD pathology, as well as other demographic and pathological covariates. Mechanisms by which micro-infarcts relate to dementia and cognition are currently unknown. Plausible hypotheses include the volume of tissue loss since micro-infarcts, despite their small volume, may represent a largely unrecognized burden in terms of number and widespread distribution (Westover et al., 2013). Micro-infarcts may also represent the latest event of a diffuse vascular process (Deramecourt et al., 2012) with deleterious tissue effects (chronic hypoperfusion, oxidative stress or inflammation).
2.2.2.
White matter lesions
Vascular leukoencephalopathy (Fig. 2D) is attributed to chronic hypoperfusion. The lesions are non-necrotic, have indistinct boundaries and are mainly located within the centrum ovale or regions adjoining the cortex. They generally spare the U-fibres (Dubas et al., 1985). Under the microscope, the damage does not appear to be very specific, with myelin loss, axonal rarefaction, astrocyte gliosis, enlargement of the perivascular spaces and microglial activation. One frequently observes arteriolosclerosis within white matter with an abnormal aspect. CAA is often accompanied by white matter lesions, which tend to be located in posterior regions. The term ‘‘leukoaraiosis’’ should only be used to describe the neuroradiological appearance of these lesions (Hachinski et al., 1987). Myelin loss is frequent in chronic cerebral small vessel diseases and microarray analyses revealed multiple associated molecular events including immune response, oligodendrocytes apoptosis, and ionic transport alterations (Simpson et al., 2009).
2.2.3.
Haemorrhage
Rupture of the vessel wall causes blood to penetrate the brain parenchyma, leading to a mass effect. Arteriolosclerosis causes deep haemorrhages within the basal ganglia, capsules or brain stem. CAA is the second most frequent cause of
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
intracerebral haemorrhage in the elderly subject; the haemorrhage is localized within the lobes and is often accompanied by cortical rupture (Charamidou et al., 2012). Cerebral microbleeds are also disease markers for the small vessels (De Reuck et al., 2011; Greenberg et al., 2009). In vessels with a diameter below 10 mm, red blood cells may extravasate into the perivascular spaces and (in some cases) the surrounding brain tissue (De Reuck et al., 2010). Old microbleeds often leave a scar with a retracted, gliotic boundary and siderophage infiltration. Although microbleeds are easily detected in brain MRI as areas of T2* hypointensity, their clinical signification remains subject to debate (Cordonnier and Van der Flier, 2011; Cordonnier et al., 2006). Cortical microbleeds are often associated with CAA. In this context, it is sometimes difficult to distinguish them from previous haemorrhagic microinfarcts. The extent of microbleeds in the basal ganglia may be overestimated by brain MRI (De Reuck et al., 2011).
2.2.4.
Changes in the perivascular spaces
Enlargement of the perivascular spaces often accompanies changes in the arteriolar walls (Deramecourt et al., 2012; Zhu et al., 2010). These changes affect both the white matter and the basal ganglia and can give these areas a punctate appearance. The underlying disease mechanism has not been characterized and may involve changes in the blood-brain barrier (induced by vascular risk factors, such as arterial hypertension) and primary atrophy of the perivascular parenchyma. These enlargements may be associated with neighbouring micro-infarcts (Fig. 2C). Even though the surrounding parenchyma is usually unaffected, some anatomic sites (the pallidum, thalamus and white matter) may display rarefaction and gliosis of the perivascular neuropile (sometimes described as an ‘‘incomplete infarct’’) (Hauw et al., 2008). Further studies of enlarged perivascular spaces are needed to determine their pathophysiological importance as well as their clinical relevance (Potter et al., 2013).
2.2.5.
Hippocampal sclerosis
Hippocampal sclerosis combines neuron loss and astrocyte gliosis of the pyramidal layer of the hippocampus. It is frequently observed in age-related dementia and certain types of frontotemporal lobe degeneration, and has also been described in vascular dementia (Dickson et al., 1994). The severity of hippocampal sclerosis of vascular origin varies; atrophy of the pyramidal neurons may constitute the first change (Gemmell et al., 2012).
3.
Types of vascular dementia
3.1.
Multi-infarct dementia
This condition is characterised by a large number of infarcts, lacunae and micro-infarcts across the two hemispheres and which affect both the cortex and subcortical structures (Jellinger, 2008; Kalaria et al., 2004). Characteristically, this type of vascular dementia is clinically accompanied by focal signs, a pseudobulbar syndrome and stepwise cognitive decline. These infarcts can have various aetiologies, some of which may occur at the same time: atherosclerosis, systemic
5
embolism and small vessel diseases such as arteriolosclerosis and CAA. It is now acknowledged that the lesion site (rather than the volume of infarcted tissue alone) has a major impact in the emergence of cognitive decline (i.e. in the associative areas, limbic areas, the white matter, etc.) (Zekry et al., 2003).
3.2.
Strategic-infarct dementia
In contrast to multi-infarct dementia, strategic-infarct dementia is caused by a single infarct (which may be a large infarct, a lacuna or a micro-infarct) (Hauw et al., 2008). There are several ‘‘strategic’’ anatomical regions: the hippocampus, the paramedian thalamus nucleus, the middle cerebral artery territory, the anterior and posterior cerebral artery territories, the caudate nucleus and the watershed regions. The most representative example of strategic-infarct dementia is the ‘‘butterfly wings’’ bilateral paramedian thalamic infarct caused by occlusion of a single pedicle originating from the first segment of a posterior cerebral artery (Castaigne et al., 1981).
3.3.
Subcortical ischaemic dementia
The boundaries of this type of vascular dementia are probably much broader than those described by Binswanger in 1894. In general, there is only slight atrophy, which manifests itself as moderate dilatation of the ventricles. In a macroscopic examination, the white matter appears to be slightly grey. Atheromatosis of the large vessels and the circle of Willis is not necessarily present. Under the microscope, vascular leukoencephalopathic lesions can be seen clearly; they are generally symmetric and associated with lacunae, enlargement of the perivascular spaces and micro-infarcts of the cortex and the basal ganglia (Kalaria et al., 2004).
3.4.
Dementia in cerebral amyloid angiopathy
It is now acknowledged that isolated CAA can cause cognitive decline, which may even progress rapidly when accompanied by granulomatous inflammation (Chung et al., 2011). For difficult-to-diagnose forms, neuropathological confirmation can be provided by a corticomeningeal biopsy.
3.5.
Mixed dementia
Cerebrovascular lesions are often associated with damage caused by AD or other neurodegenerative diseases (Jellinger, 2007; Jellinger and Attems, 2003, 2005). Many definitions of mixed dementia have been proposed since the initial descriptions by Delay and Brion in the 1960s, emphasizing how difficult it is to define a lesional threshold beyond which neuropathological changes are considered to be significant. Hence, if mixed dementia were to be defined as a combination of AD with any type of cerebrovascular lesion, then this entity would account for over 90% of AD cases in neuropathological series (Ince and Fernando, 2003; Roman, 2002a, b). In practice, significant vascular involvement (including infarcts and vascular leukoencephalopathy) is found in about two thirds of AD cases – making mixed dementia the most frequent cause of dementia in the elderly subject (Ince and Fernando, 2003).
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
6
revue neurologique xxx (2013) xxx–xxx
This combination of lesions does have clinical relevance. In fact, it is well established that the presence of cerebrovascular lesions aggravates the severity of early AD. In the presence of cerebrovascular lesions, the AD lesion burden found at the onset of dementia is lower than that observed in ‘‘pure’’ AD (Esiri et al., 1999; Schneider et al., 2009; Zekry et al., 2002). This combination of lesions is not limited to AD and has also been described in dementia with Lewy bodies (Jellinger and Attems, 2008).
4. Current limitations and perspectives in the neuropathological diagnosis of vascular dementia Vascular dementia is a heterogeneous entity on the clinical and pathological levels. The cerebrovascular lesions themselves have many causes. Multidisciplinary research is still complicated by terminological difficulties (Grinberg and Heinsen, 2010). A given lesion may have one definition for a neuropathologist and another for a neuroradiologist. Likewise, different neuropathological lesions may have the same neuroradiological appearance. There is also a more specifically neuropathological difficulty: the inability to sample the whole encephalon for microscopic examination. Hence, a lesion of interest may escape examination. A number of procedures for mitigating this risk have been suggested, albeit at the expense of greater technical complexity (Gold et al., 2007; Ihara et al., 2010). Some research groups have suggest that brain sampling could benefit from imaging techniques, such as the MRI investigation of fixed anatomical segments (De Reuck et al., 2011). In the absence of consensus on neuropathological criteria, diagnosis of vascular dementia and mixed dementia must absolutely be based on clinical and pathological expert analyses (Hachinski et al., 2006). In fact, it appears to be tricky (and perhaps even illogical) to define a threshold beyond which the cerebrovascular lesion burden should be considered to be significantly associated with cognitive decline. The high incidence of cerebrovascular lesions in cognitively normal elderly subjects illustrates this very well. Any such definition would have to take account of many different variables: the lesion site, the volume of damaged tissue and the extent of the associated neurodegenerative lesions, as well as all the compensatory factors that the brain can develop. These difficulties will only be resolved by constituting large, prospective cohorts (with frequent brain biopsy sampling) that enable cerebrovascular lesions to be described as accurately as possible (Gorelick et al., 2011). Guidelines on harmonizing the neuropathological inventory of lesions of interest have been published (Hachinski et al., 2006). One way of avoiding topographic and volume heterogeneity when quantifying lesions would be to stage the latter according to their natural history, as has been suggested for disseminated conditions like small vessel disease (Deramecourt et al., 2012). In this cohort of 135 post-mortem brains from patients with dementia, the precise inventory of vascular changes suggested a sequential worsening ranging from initial vessel wall changes, followed by perivascular spaces modifications, white matter loss and eventually infarcts. This conceptual model of cerebral small vessel disease was transformed into an
operational staging system for use in evaluating the vascular contribution in cognitive disorders. This staging system has already been used in some clinical-pathological studies (Craggs et al., 2013; Gemmell et al., 2012) but further data are needed to evaluate its relevance for diagnosis or research practice.
Disclosure of interest The author declares that he has no conflicts of interest concerning this article.
references
Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011;42:722–7. Castaigne P, Lhermitte F, Buge A, Escourolle R, Hauw JJ, Lyon-Caen O. Paramedian thalamic and midbrain infarct: clinical and neuropathological study. Ann Neurol 1981;10:127–48. Charamidou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited; recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012;83:124–37. Chung KK, Anderson NE, Hutchinson D, Synek B, Barber PA. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry 2011;82:20–6. Cordonnier C, Van der Flier WM. Brain microbleeds and Alzheimer’s disease: innocent observation or key player? Brain 2011;134:335–44. Cordonnier C, van der Flier WM, Sluimer JD, Leys D, Barkhof F, Scheltens P. Prevalence and severity of microbleeds in a memory clinic setting. Neurology 2006;66:1356–60. Craggs LJ, Hagel C, Kuhlenbaeumer G, Borjesson-Hanson A, Andersen O, Viitanen M, et al. Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases. Brain Pathol 2013;23(5):547–57. De Reuck J, Auger F, Cordonnier C, Deramecourt V, Durieux N, Pasquier F, et al. Comparison of 7.0T T2*-magnetic resonance imaging of cerebral bleeds in post mortem sections of ALzheimer’s patients with neuropathological correlates. Cerebrovasc Dis 2011;31:511–7. De Reuck J, Deramecourt V, Cordonnier C, Leys D, Pasquier F, Maurage CA. Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study. J Neurol Sci 2010;300:63–6. Deramecourt V, Slade JY, Oakley AE, Perry RH, Ince PG, Maurage CA, et al. Staging and natural history of cerebrovascular pathology in dementia. Neurology 2012;78:1043–50. Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Grober E, et al. Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 1994;88:212–21. Dubas F, Gray F, Roullet E, Escourolle R. Leucoence´phalopathies arte´riopathiques. Rev Neurol 1985;141:93–108. Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology 1996;46:1592–6. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 1999;354:919–20.
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
Ferrer I. Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J Neurol Sci 2010;299:139–49. Gemmell E, Bosomworth H, Allan L, Hall R, Khundakar A, Oakley AE, et al. Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. Stroke 2012;43:808–14. Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E. Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 2007;130:2830–6. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42:2672–713. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, AlShahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–74. Grinberg L, Heinsen H. Toward a pathological definition of vascular dementia. J Neurol Sci 2010;299:136–8. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006;37: 2220–41. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974;2:207–10. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44:21–3. Hauw JJ, De Girolami U, Zekry D. The neuropathology of vascular and mixed dementia and vascular cognitive impairment. Handb Clin Neurol 2008;89:687–703. Ihara M, Polvikoski TM, Hall R, Slade JY, Perry RH, Oakley AE, et al. Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol 2010;119: 579–89. Ince PG, Fernando MS. Neuropathology of vascular cognitive impairment and vascular dementia. Int Psychogeriatr 2003;15(Suppl. 1):71–5. Jellinger KA. The enigma of mixed dementia. Alzheimers Dement 2007;3:40–53. Jellinger KA. Morphologic diagnosis of ‘‘vascular dementia’’ – a critical update. J Neurol Sci 2008;270:1–12. Jellinger KA, Attems J. Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol 2003;105:14–7. Jellinger KA, Attems J. Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease. J Neurol Sci 2005;229-230:37–41. Jellinger KA, Attems J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol 2008;115:427–36. Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 2004;226:75–80. Keage HA, Carare RO, Friedland RP, Ince PG, Love S, Nicoll JA, et al. Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review. BMC Neurol 2009;9:3. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927–31.
Neuropathology group of the Medical Research Council Cognitive Function Ageing Study. Pathological correlates of late-onset dementia in a multicentre community-based population in England and Wales. Lancet 2001;357:169–75. O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurol 2003;2:89–98. Pantoni L. Cerebral small vessel disease: from pathogenesis and characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. Potter GM, Doubal FN, Jackson CA, Chappell FM, Dennis MS, Wardlaw JM. Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke 2013. http://dx.doi.org/ 10.1111/ijs.12054 [Epub ahead of print 2013 May 22]. Roman GC. On the history of lacunes, e´tat crible´, and the white matter lesions of vascular dementia. Cerebrovasc Dis 2002a;13:1–6. Roman GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci 2002b;203-204:7–10. Roman GC, Tatemichi T, Erkinjuntti T, Cummings JL, Masdeu J, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINCDS-AIREN International Workshop. Neurology 1993;43:250–60. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The neuropathology of older person with and without dementia from community versus clinic cohorts. J Alzheimers Dis 2009;18:691–701. Simpson JE, Hosny O, Wharton SB, Heath PR, Holden H, Fernando MS, et al. Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways. Stroke 2009;40:369–75. Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Microinfarcts: the invisible lesions. Lancet Neurol 2012;11:272–82. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 2003;62:1287–301. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 2002;61:282–93. Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 2008;115:599–609. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11:205–42. Westover MB, Bianchi MT, Yang C, Schneider JA, Greenberg SM. Estimating cerebral microinfarct burden from autopsy samples. Neurology 2013;80:1365–9. White L. Brains lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis 2009;18:713–25. Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R, et al. The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy. Neurobiol Aging 2003;24:213–9. Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol 2002;103:481–7. Zhu YC, Tzourio C, Soumare A, Mazoyer B, Dufouil C, Chabriat H. Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease. A population-based study. Stroke 2010;41:2483–90.
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
7
Available online at
www.sciencedirect.com
International meeting of the French society of neurology 2013
Vascular neuropathology and cognitive decline Neuropathologie vasculaire et de´clin cognitif V. Deramecourt Centre me´moire de ressources et de recherche, CNR maladie d’Alzheimer du sujet jeune, de´partement d’histologie, EA1046, laboratoire d’excellence DISTALZ, universite´ Lille-Nord-de-France, centre hospitalier re´gional universitaire de Lille, hoˆpital Roger-Salengro, rue Emile-Laine, 59037 Lille, France
info article
abstract
Article history:
Cerebrovascular disease is an important cause of cognitive decline and dementia. Despite
Received 27 May 2013
numerous epidemiological, clinical, neuroimaging and neuropathological studies, the link
Received in revised form
between cerebrovascular lesions and their impact on cognition and behavior is still a matter
2 July 2013
of debate. Cerebrovascular lesions are heterogeneous and most descriptive studies dis-
Accepted 9 July 2013
tinguish vessel wall modifications, perivascular space modifications, white matter changes,
Available online xxx
and infarcts as the main features of vascular dementia. However, to date there is still no consensual criteria for the neuropathological diagnosis of vascular or mixed dementia. The
Keywords:
diagnosis of these conditions still relies on both clinical and neuropathological expertise. # 2013 Published by Elsevier Masson SAS.
Arteriolosclerosis Cerebral amyloid angiopathy Micro-infarcts Lacunar infarct Mots cle´s : Arterioloscle´rose Angiopathie amyloı¨de ce´re´brale Microinfarctus Lacune
r e´ s u m e´ Les pathologies ce´re´brovasculaires sont une cause importante de de´clin cognitif et de de´mence. Malgre´ de nombreux travaux e´pide´miologiques, cliniques, neuroradiologiques et neuropathologiques, les liens entre les le´sions ce´re´brovasculaires et leurs conse´quences cognitives et comportementales sont encore de´battus. L’e´ventail le´sionnel est large depuis les modifications des parois vasculaires elles-meˆmes, les modifications des espaces pe´rivasculaires, les le´sions de substance blanche, jusqu’aux infarctus tissulaires constitue´s. En l’absence de crite`res neuropathologiques consensuels de de´mence vasculaire, ce diagnostic, comme celui de de´mence mixte, doit absolument reposer sur une expertise clinicopathologique. # 2013 Publie´ par Elsevier Masson SAS.
Cerebrovascular lesions and their causal links with the emergence of cognitive decline probably constitute one of the most complex subjects in the neuropathology of dementia (Ferrer, 2010). There are three levels of explanation for this complexity. Firstly, the cerebrovascular lesions and the underlying disease mechanisms are very heterogeneous and
range from vessel wall changes to tissue damage itself. Secondly, there is still much debate over the causal relationships that drive cerebrovascular lesions and their harmful effects on cognitive function. Lastly, there is not yet any consensus on the most relevant way of assessing and quantifying cerebrovascular lesions, which therefore prevents
E-mail address: [email protected]. 0035-3787/$ – see front matter # 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2013.07.008 Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
2
revue neurologique xxx (2013) xxx–xxx
the large-scale harmonization of clinical and pathological studies.
1.
A historical overview
The 17th century physician Thomas Willis was probably the first person to describe post-stroke cognitive impairment. In the early 20th century, the famous neuropsychiatrists and pathologists Aloı¨s Alzheimer and Otto Binswanger drew a distinction between cerebrovascular lesions and syphilitic dementia. Kraepelin considered that the most frequent cause of senile dementia was arteriosclerosis, inducing a progressive narrowing of the vessels, a reduction in cerebral blood flow and neuron loss. In 1970, Tomlinson et al. published the first large study on ‘‘arteriosclerotic dementia’’ and showed that cerebrovascular lesions constituted a major cause of cognitive decline in about a third of elderly demented patients and, indeed, the only cause in about a sixth of these patients (Tomlinson et al., 1970). Tomlinson et al.’s observations were mainly based on the presence of brain infarcts: they suggested that a volume threshold of 100 mL of infarcted tissue was associated with a high risk of dementia. Hachinski completed this viewpoint by introducing the concept of multi-infarct dementia in 1974 (Hachinski et al., 1974). However, it then became clear that lesions other than infarcts could also contribute to cognitive decline. Hence, ‘‘multi-infarct dementia’’ was replaced first by the more general concept of ‘‘vascular dementia’’ (Roman et al., 1993) and then by the term ‘‘vascular cognitive impairment’’ (Gorelick et al., 2011; O’Brien et al., 2003).
2.
Cerebrovascular lesions of interest
2.1.
Vessel wall changes
The vessel wall changes most frequently linked to vascular dementia are cerebral arteriosclerosis, cerebral arteriolosclerosis and cerebral amyloid angiopathy (CAA). The frequency and the severity of these changes increase with age.
2.1.1.
Arteriosclerosis
Arteriosclerosis affects the large and medium-sized arteries of the brain and results in thickening of the tunica intima, with the accumulation of lipids (mainly cholesterol) and proteins within the vessel wall (Fig. 1B). This process is followed by the calcification of atheromatous plaques and fibrosis of the vessel wall. Plaque rupture frequently induces local thrombosis and complication of the latter by a large infarct. Embolization of the atherogenic thrombus creates an infarct of variable size.
2.1.2.
Arteriolosclerosis/lipohyalinosis
Arteriolosclerosis affects arteries with a diameter of between 40 and 150 mm and manifests itself as concentric, hyalinised thickening of the arteriolar wall, loss of smooth muscle cells and disorganisation of the tunica media (Fig. 1C) (Pantoni, 2010). Lipohyalinosis has a fairly similar appearance, although the hyalinosis and fibrosis are asymmetrically distributed and there may be fibrinoid necrosis of the arteriolar wall.
Arteriolosclerosis and lipohyalinosis are complicated by lacunar infarcts, micro-infarcts, microbleeds and/or large haemorrhages. They appear early in the course of the disease in the arterioles of the basal ganglia and then extend to the white matter, the leptomeningeal arterioles and (in severe cases) the arterioles of the cerebellum and the brain stem (Thal et al., 2003). In general, the cortical arterioles are not affected.
2.1.3.
Cerebral amyloid angiopathy
Sporadic CAA is characterized by the deposition of Ab peptides within the vessel wall. Whereas the intraparenchymatous amyloid plaques in Alzheimer’s disease (AD) are mainly constituted of Ab-42 peptide, vascular deposits (and particularly those in the leptomeningeal vessels) are mainly constituted of Ab-40 and form concentric layers that replace the smooth muscle cells. The amyloid deposits in arterioles and small cortical arteries are constituted of a mixture of Ab40 and Ab-42, whereas those affecting the capillaries are mainly composed of Ab-42 (Thal et al., 2008). In severe forms, the vessel wall is totally remodelled and weakened, with shrinkage of the lumen and the development of microaneurysms and fibrinoid necrosis (Fig. 1D). A neuropathological examination also reveals haemorrhagic complications (microbleeds and perivascular and leptomeningeal haemosiderin deposits) and ischaemic complications (cortical micro-infarcts and myelin loss). It has been suggested that two types of sporadic CAA exist: CAA type 1 is characterized by Ab deposits in cortical capillaries (in the presence or absence of damage to the other types of vessels), whereas in CAA type 2, deposits are limited to the leptomeningeal and cortical arteries and arterioles and (more rarely) venules (Thal et al., 2002). The e4 and e2 genotypes of APOE are associated with CAA types 1 and 2, respectively. The occipital lobe is the most frequently affected area, followed by the frontal, temporal and parietal lobes. The cerebellum may be damaged in late-stage disease, whereas the basal ganglia, the white matter and the brain stem are not usually affected (Thal et al., 2008). The prevalence of CAA in autopsy cohorts varies between 20 and 40% in non-demented cases and between 50 and 60% in demented cases (Keage et al., 2009). CAA is strongly associated with increasing age. CAA is almost always present in AD cases, but only 25% of them exhibit severe forms of the disease (Ellis et al., 1996). There is no etiological link between CAA and the classical vascular risk factors, despite arterial hypertension may aggravate its hemorrhagic complications. The only known genetic risk factors of CAA are E4 and E2 genotypes of APOE gene. CAA probably represents a cause of cognitive decline by itself since the association between CAA and dementia persists after adjustment for age and the severity of associated neuritic plaques (Neuropathology group of the MRC-CFAS, 2001). Thus, CAA is to be considered as a pathophysiological process located at the crossroad between microvascular and neurodegenerative pathologies.
2.1.4.
Hereditary microangiopathies
These conditions, mostly represented by the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), are usually characterized by
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
3
Fig. 1 – Main vascular modifications associated with vascular cognitive impairment. A. Normal microscopic appearance of a deep white matter artery. The nuclei of smooth muscle cells are well seen (arrow). B. Atheroma of the circle of Willis arteries. Atheromatous plaque (asterisk) is visible within the tunica media of this artery. C. Arteriolosclerosis/ lipohyalinosis. The tunica media is thickened (arrow) with severe loss of smooth muscle cells. D. Cerebral amyloid angiopathy. The vessel wall is severely modified by the accumulation of eosinophilic material corresponding to fibrillar Ab deposits (arrow). Amyloid deposition is also present in the surrounding neuropile (asterisk). Scale bar = 100 mm for all images.
progressive dementia. This specific chapter will be developed elsewhere.
2.1.5.
Other rare microangiopathies
These conditions are likely to lead to the occlusion of brain microvessels. Some diseases have an inflammatory aetiology (e.g. necrotizing angiitis, systemic erythematosus lupus, Wegener’s granulomatosis with polyangiitis and polyarteritis nodosa). Primary angiitis of the central nervous system is a related condition. Other microvessel diseases are variously caused by toxins (vasoconstrictors and drugs), tumours (endovascular lymphoma), malformations (Moyamoya disease) and genetic factors (rare Icelandic-type amyloidosis, Finnish hereditary amyloidosis and familial British dementia with amyloid angiopathy, etc.).
2.2.
Parenchymatous lesions
2.2.1.
Infarct
Brain infarcts are areas of parenchymatous necrosis caused by impaired circulation. In post-mortem analyses, the incidence of infarct increases up to the age of 91 and then levels off. The
National Institute of Neurological Disorders and Stroke – Canadian Stroke Network recommended classifying brain infarcts by size, in order to facilitate radiological correlations (Hachinski et al., 2006). Large infarcts have a greatest dimension of over 1 cm or a volume of more than 1.5 cm3 and can be seen in conventional magnetic resonance imaging (MRI). Micro-infarcts have a greatest dimension below 0.5 cm and are not generally visible in MRI (Smith et al., 2012). These infarcts have either thrombotic or embolic aetiologies. Cortical micro-infarcts (Fig. 2B) are caused by the occlusion of cortical perforating arteries and are often related to a small vessel disease, such as progressing arteriolosclerosis or an amyloid angiopathy (Kovari et al., 2007). As the number of microinfarcts increases, the brain cortex takes on a granular appearance, with an irregular decrease in the thickness of the cortical ribbon. Granular atrophy of the cerebral cortex generally predominates at the junction between the main cerebral vascular territories. Lacunae (Fig. 2A) correspond to small foci of deep infarct that are mainly related to arteriolosclerosis of the deep perforating arteries or (more rarely) embolic aetiologies (Roman, 2002a, b). The terms ‘‘lacunar infarct’’ and ‘‘ischaemic
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
4
revue neurologique xxx (2013) xxx–xxx
Fig. 2 – Macroscopic and microscopic lesions with a vascular aetiology. A. The macroscopic appearance of a lacuna in the lentiform nucleus (arrow), with cribriform changes within the thalamus (arrow heads) and greyish discoloration of the frontal white matter, sparing the U-fibres and suggesting vascular leukoencephalopathy (asterisk). B. A cortical microinfarct (HE staining), with boundaries indicated by arrows. C. ‘‘e´tat crible´’’ (HE staining) of the thalamus under the microscope, combining a micro-infarct (arrow) and enlargement of the perivascular spaces on the left side of the image. D. The microscopic appearance of vascular leukoencephalopathy, with myelin loss and a decrease in the oligodendroglial density (Luxol Fast Blue staining). E. The microscopic appearance (HE staining) of lipohyalinosis, with concentric thickening of the arteriolar wall and loss of the tunica media’s smooth muscle cells (arrow). The surrounding white matter is pigmented by haemosiderin (HE staining). Scale bar = 100 mm for all images.
lacuna’’ are sometimes used to distinguish this condition from the state in which the perivascular spaces are widened (Hauw et al., 2008). The effect of infarcts on cognitive status has been evaluated in several clinicopathological cohorts such as the Honolulu-Asia aging study, the MRC-CFAS study in the UK, and the Religious Order Study (ROS) in Chicago (Smith et al., 2012). Lacunar infarcts are probably less associated with cognitive decline than micro-infarcts (White, 2009). Microinfarcts are common, affecting almost one-third of all subjects from the ROS cohort, and present in one-third of those with dementia and one-quarter of those without (Arvanitakis et al., 2011). In this study, micro-infarcts, especially multiple cortical infarcts, independently increased odds of dementia even after accounting for macro infarcts and level of AD pathology, as well as other demographic and pathological covariates. Mechanisms by which micro-infarcts relate to dementia and cognition are currently unknown. Plausible hypotheses include the volume of tissue loss since micro-infarcts, despite their small volume, may represent a largely unrecognized burden in terms of number and widespread distribution (Westover et al., 2013). Micro-infarcts may also represent the latest event of a diffuse vascular process (Deramecourt et al., 2012) with deleterious tissue effects (chronic hypoperfusion, oxidative stress or inflammation).
2.2.2.
White matter lesions
Vascular leukoencephalopathy (Fig. 2D) is attributed to chronic hypoperfusion. The lesions are non-necrotic, have indistinct boundaries and are mainly located within the centrum ovale or regions adjoining the cortex. They generally spare the U-fibres (Dubas et al., 1985). Under the microscope, the damage does not appear to be very specific, with myelin loss, axonal rarefaction, astrocyte gliosis, enlargement of the perivascular spaces and microglial activation. One frequently observes arteriolosclerosis within white matter with an abnormal aspect. CAA is often accompanied by white matter lesions, which tend to be located in posterior regions. The term ‘‘leukoaraiosis’’ should only be used to describe the neuroradiological appearance of these lesions (Hachinski et al., 1987). Myelin loss is frequent in chronic cerebral small vessel diseases and microarray analyses revealed multiple associated molecular events including immune response, oligodendrocytes apoptosis, and ionic transport alterations (Simpson et al., 2009).
2.2.3.
Haemorrhage
Rupture of the vessel wall causes blood to penetrate the brain parenchyma, leading to a mass effect. Arteriolosclerosis causes deep haemorrhages within the basal ganglia, capsules or brain stem. CAA is the second most frequent cause of
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
intracerebral haemorrhage in the elderly subject; the haemorrhage is localized within the lobes and is often accompanied by cortical rupture (Charamidou et al., 2012). Cerebral microbleeds are also disease markers for the small vessels (De Reuck et al., 2011; Greenberg et al., 2009). In vessels with a diameter below 10 mm, red blood cells may extravasate into the perivascular spaces and (in some cases) the surrounding brain tissue (De Reuck et al., 2010). Old microbleeds often leave a scar with a retracted, gliotic boundary and siderophage infiltration. Although microbleeds are easily detected in brain MRI as areas of T2* hypointensity, their clinical signification remains subject to debate (Cordonnier and Van der Flier, 2011; Cordonnier et al., 2006). Cortical microbleeds are often associated with CAA. In this context, it is sometimes difficult to distinguish them from previous haemorrhagic microinfarcts. The extent of microbleeds in the basal ganglia may be overestimated by brain MRI (De Reuck et al., 2011).
2.2.4.
Changes in the perivascular spaces
Enlargement of the perivascular spaces often accompanies changes in the arteriolar walls (Deramecourt et al., 2012; Zhu et al., 2010). These changes affect both the white matter and the basal ganglia and can give these areas a punctate appearance. The underlying disease mechanism has not been characterized and may involve changes in the blood-brain barrier (induced by vascular risk factors, such as arterial hypertension) and primary atrophy of the perivascular parenchyma. These enlargements may be associated with neighbouring micro-infarcts (Fig. 2C). Even though the surrounding parenchyma is usually unaffected, some anatomic sites (the pallidum, thalamus and white matter) may display rarefaction and gliosis of the perivascular neuropile (sometimes described as an ‘‘incomplete infarct’’) (Hauw et al., 2008). Further studies of enlarged perivascular spaces are needed to determine their pathophysiological importance as well as their clinical relevance (Potter et al., 2013).
2.2.5.
Hippocampal sclerosis
Hippocampal sclerosis combines neuron loss and astrocyte gliosis of the pyramidal layer of the hippocampus. It is frequently observed in age-related dementia and certain types of frontotemporal lobe degeneration, and has also been described in vascular dementia (Dickson et al., 1994). The severity of hippocampal sclerosis of vascular origin varies; atrophy of the pyramidal neurons may constitute the first change (Gemmell et al., 2012).
3.
Types of vascular dementia
3.1.
Multi-infarct dementia
This condition is characterised by a large number of infarcts, lacunae and micro-infarcts across the two hemispheres and which affect both the cortex and subcortical structures (Jellinger, 2008; Kalaria et al., 2004). Characteristically, this type of vascular dementia is clinically accompanied by focal signs, a pseudobulbar syndrome and stepwise cognitive decline. These infarcts can have various aetiologies, some of which may occur at the same time: atherosclerosis, systemic
5
embolism and small vessel diseases such as arteriolosclerosis and CAA. It is now acknowledged that the lesion site (rather than the volume of infarcted tissue alone) has a major impact in the emergence of cognitive decline (i.e. in the associative areas, limbic areas, the white matter, etc.) (Zekry et al., 2003).
3.2.
Strategic-infarct dementia
In contrast to multi-infarct dementia, strategic-infarct dementia is caused by a single infarct (which may be a large infarct, a lacuna or a micro-infarct) (Hauw et al., 2008). There are several ‘‘strategic’’ anatomical regions: the hippocampus, the paramedian thalamus nucleus, the middle cerebral artery territory, the anterior and posterior cerebral artery territories, the caudate nucleus and the watershed regions. The most representative example of strategic-infarct dementia is the ‘‘butterfly wings’’ bilateral paramedian thalamic infarct caused by occlusion of a single pedicle originating from the first segment of a posterior cerebral artery (Castaigne et al., 1981).
3.3.
Subcortical ischaemic dementia
The boundaries of this type of vascular dementia are probably much broader than those described by Binswanger in 1894. In general, there is only slight atrophy, which manifests itself as moderate dilatation of the ventricles. In a macroscopic examination, the white matter appears to be slightly grey. Atheromatosis of the large vessels and the circle of Willis is not necessarily present. Under the microscope, vascular leukoencephalopathic lesions can be seen clearly; they are generally symmetric and associated with lacunae, enlargement of the perivascular spaces and micro-infarcts of the cortex and the basal ganglia (Kalaria et al., 2004).
3.4.
Dementia in cerebral amyloid angiopathy
It is now acknowledged that isolated CAA can cause cognitive decline, which may even progress rapidly when accompanied by granulomatous inflammation (Chung et al., 2011). For difficult-to-diagnose forms, neuropathological confirmation can be provided by a corticomeningeal biopsy.
3.5.
Mixed dementia
Cerebrovascular lesions are often associated with damage caused by AD or other neurodegenerative diseases (Jellinger, 2007; Jellinger and Attems, 2003, 2005). Many definitions of mixed dementia have been proposed since the initial descriptions by Delay and Brion in the 1960s, emphasizing how difficult it is to define a lesional threshold beyond which neuropathological changes are considered to be significant. Hence, if mixed dementia were to be defined as a combination of AD with any type of cerebrovascular lesion, then this entity would account for over 90% of AD cases in neuropathological series (Ince and Fernando, 2003; Roman, 2002a, b). In practice, significant vascular involvement (including infarcts and vascular leukoencephalopathy) is found in about two thirds of AD cases – making mixed dementia the most frequent cause of dementia in the elderly subject (Ince and Fernando, 2003).
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7
6
revue neurologique xxx (2013) xxx–xxx
This combination of lesions does have clinical relevance. In fact, it is well established that the presence of cerebrovascular lesions aggravates the severity of early AD. In the presence of cerebrovascular lesions, the AD lesion burden found at the onset of dementia is lower than that observed in ‘‘pure’’ AD (Esiri et al., 1999; Schneider et al., 2009; Zekry et al., 2002). This combination of lesions is not limited to AD and has also been described in dementia with Lewy bodies (Jellinger and Attems, 2008).
4. Current limitations and perspectives in the neuropathological diagnosis of vascular dementia Vascular dementia is a heterogeneous entity on the clinical and pathological levels. The cerebrovascular lesions themselves have many causes. Multidisciplinary research is still complicated by terminological difficulties (Grinberg and Heinsen, 2010). A given lesion may have one definition for a neuropathologist and another for a neuroradiologist. Likewise, different neuropathological lesions may have the same neuroradiological appearance. There is also a more specifically neuropathological difficulty: the inability to sample the whole encephalon for microscopic examination. Hence, a lesion of interest may escape examination. A number of procedures for mitigating this risk have been suggested, albeit at the expense of greater technical complexity (Gold et al., 2007; Ihara et al., 2010). Some research groups have suggest that brain sampling could benefit from imaging techniques, such as the MRI investigation of fixed anatomical segments (De Reuck et al., 2011). In the absence of consensus on neuropathological criteria, diagnosis of vascular dementia and mixed dementia must absolutely be based on clinical and pathological expert analyses (Hachinski et al., 2006). In fact, it appears to be tricky (and perhaps even illogical) to define a threshold beyond which the cerebrovascular lesion burden should be considered to be significantly associated with cognitive decline. The high incidence of cerebrovascular lesions in cognitively normal elderly subjects illustrates this very well. Any such definition would have to take account of many different variables: the lesion site, the volume of damaged tissue and the extent of the associated neurodegenerative lesions, as well as all the compensatory factors that the brain can develop. These difficulties will only be resolved by constituting large, prospective cohorts (with frequent brain biopsy sampling) that enable cerebrovascular lesions to be described as accurately as possible (Gorelick et al., 2011). Guidelines on harmonizing the neuropathological inventory of lesions of interest have been published (Hachinski et al., 2006). One way of avoiding topographic and volume heterogeneity when quantifying lesions would be to stage the latter according to their natural history, as has been suggested for disseminated conditions like small vessel disease (Deramecourt et al., 2012). In this cohort of 135 post-mortem brains from patients with dementia, the precise inventory of vascular changes suggested a sequential worsening ranging from initial vessel wall changes, followed by perivascular spaces modifications, white matter loss and eventually infarcts. This conceptual model of cerebral small vessel disease was transformed into an
operational staging system for use in evaluating the vascular contribution in cognitive disorders. This staging system has already been used in some clinical-pathological studies (Craggs et al., 2013; Gemmell et al., 2012) but further data are needed to evaluate its relevance for diagnosis or research practice.
Disclosure of interest The author declares that he has no conflicts of interest concerning this article.
references
Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011;42:722–7. Castaigne P, Lhermitte F, Buge A, Escourolle R, Hauw JJ, Lyon-Caen O. Paramedian thalamic and midbrain infarct: clinical and neuropathological study. Ann Neurol 1981;10:127–48. Charamidou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited; recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012;83:124–37. Chung KK, Anderson NE, Hutchinson D, Synek B, Barber PA. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry 2011;82:20–6. Cordonnier C, Van der Flier WM. Brain microbleeds and Alzheimer’s disease: innocent observation or key player? Brain 2011;134:335–44. Cordonnier C, van der Flier WM, Sluimer JD, Leys D, Barkhof F, Scheltens P. Prevalence and severity of microbleeds in a memory clinic setting. Neurology 2006;66:1356–60. Craggs LJ, Hagel C, Kuhlenbaeumer G, Borjesson-Hanson A, Andersen O, Viitanen M, et al. Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases. Brain Pathol 2013;23(5):547–57. De Reuck J, Auger F, Cordonnier C, Deramecourt V, Durieux N, Pasquier F, et al. Comparison of 7.0T T2*-magnetic resonance imaging of cerebral bleeds in post mortem sections of ALzheimer’s patients with neuropathological correlates. Cerebrovasc Dis 2011;31:511–7. De Reuck J, Deramecourt V, Cordonnier C, Leys D, Pasquier F, Maurage CA. Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study. J Neurol Sci 2010;300:63–6. Deramecourt V, Slade JY, Oakley AE, Perry RH, Ince PG, Maurage CA, et al. Staging and natural history of cerebrovascular pathology in dementia. Neurology 2012;78:1043–50. Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Grober E, et al. Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 1994;88:212–21. Dubas F, Gray F, Roullet E, Escourolle R. Leucoence´phalopathies arte´riopathiques. Rev Neurol 1985;141:93–108. Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology 1996;46:1592–6. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 1999;354:919–20.
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
NEUROL-1127; No. of Pages 7 revue neurologique xxx (2013) xxx–xxx
Ferrer I. Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J Neurol Sci 2010;299:139–49. Gemmell E, Bosomworth H, Allan L, Hall R, Khundakar A, Oakley AE, et al. Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. Stroke 2012;43:808–14. Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E. Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 2007;130:2830–6. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42:2672–713. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, AlShahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–74. Grinberg L, Heinsen H. Toward a pathological definition of vascular dementia. J Neurol Sci 2010;299:136–8. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006;37: 2220–41. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974;2:207–10. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44:21–3. Hauw JJ, De Girolami U, Zekry D. The neuropathology of vascular and mixed dementia and vascular cognitive impairment. Handb Clin Neurol 2008;89:687–703. Ihara M, Polvikoski TM, Hall R, Slade JY, Perry RH, Oakley AE, et al. Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol 2010;119: 579–89. Ince PG, Fernando MS. Neuropathology of vascular cognitive impairment and vascular dementia. Int Psychogeriatr 2003;15(Suppl. 1):71–5. Jellinger KA. The enigma of mixed dementia. Alzheimers Dement 2007;3:40–53. Jellinger KA. Morphologic diagnosis of ‘‘vascular dementia’’ – a critical update. J Neurol Sci 2008;270:1–12. Jellinger KA, Attems J. Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol 2003;105:14–7. Jellinger KA, Attems J. Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease. J Neurol Sci 2005;229-230:37–41. Jellinger KA, Attems J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol 2008;115:427–36. Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 2004;226:75–80. Keage HA, Carare RO, Friedland RP, Ince PG, Love S, Nicoll JA, et al. Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review. BMC Neurol 2009;9:3. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927–31.
Neuropathology group of the Medical Research Council Cognitive Function Ageing Study. Pathological correlates of late-onset dementia in a multicentre community-based population in England and Wales. Lancet 2001;357:169–75. O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurol 2003;2:89–98. Pantoni L. Cerebral small vessel disease: from pathogenesis and characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. Potter GM, Doubal FN, Jackson CA, Chappell FM, Dennis MS, Wardlaw JM. Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke 2013. http://dx.doi.org/ 10.1111/ijs.12054 [Epub ahead of print 2013 May 22]. Roman GC. On the history of lacunes, e´tat crible´, and the white matter lesions of vascular dementia. Cerebrovasc Dis 2002a;13:1–6. Roman GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci 2002b;203-204:7–10. Roman GC, Tatemichi T, Erkinjuntti T, Cummings JL, Masdeu J, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINCDS-AIREN International Workshop. Neurology 1993;43:250–60. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The neuropathology of older person with and without dementia from community versus clinic cohorts. J Alzheimers Dis 2009;18:691–701. Simpson JE, Hosny O, Wharton SB, Heath PR, Holden H, Fernando MS, et al. Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways. Stroke 2009;40:369–75. Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Microinfarcts: the invisible lesions. Lancet Neurol 2012;11:272–82. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 2003;62:1287–301. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 2002;61:282–93. Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 2008;115:599–609. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11:205–42. Westover MB, Bianchi MT, Yang C, Schneider JA, Greenberg SM. Estimating cerebral microinfarct burden from autopsy samples. Neurology 2013;80:1365–9. White L. Brains lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis 2009;18:713–25. Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R, et al. The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy. Neurobiol Aging 2003;24:213–9. Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol 2002;103:481–7. Zhu YC, Tzourio C, Soumare A, Mazoyer B, Dufouil C, Chabriat H. Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease. A population-based study. Stroke 2010;41:2483–90.
Please cite this article in press as: Deramecourt V, Vascular neuropathology and cognitive decline. Revue neurologique (2013), http://dx.doi.org/ 10.1016/j.neurol.2013.07.008
7