In this article, I review the brief history of our current understanding of VaD, various criteria incorporating clinical, neuropsychological and pathological features that have been proposed over the years and key vascular lesions and tissue changes, which contribute to dementia. I convey some opinions about brain sampling and consider some of the rarer causes of VCI and VaD and how these can be investigated.
Vascular causes of dementia and their contribution to neurodegenerative processes have not been widely emphasised. Both Alzheimer and Kraeplin had reasoned that old age-associated progressive hardening of the arteries lead to arteriosclerotic dementia. The diagnosis of arteriosclerotic dementia often superseded that of AD, which became to be frequently diagnosed in the late s on whether it is a form of pre-senile or senile dementia.
VaD or cerebrovascular dementia implies a clinically diagnosed dementia syndrome comprising subtypes with both ischemic and haemorrhagic aetiologies [ ]. As AD became more commonly recognised, VaD was often similarly characterised as a primary memory-associated dementia but involving vascular causes.
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Common and uncommon causes of stroke pathophysiology associated with cognitive impairment or dementia. Small vessel dementia; subcortical ischaemic vascular dementia; strategic infarct dementia. Arterial dissections carotid, vertebral and intracranial , fibromuscular dysplasia, dolichoectatic basilar artery, large artery kinking and coiling, radiation induced angiopathy, moyamoya disease. No pattern of brain infarctions: haemodynamic, thromboembolic, or due to occlusion of a perforating artery.
Subarachnoid haemorrhage; lacunar infarcts, PVS. Fabry disease, familial hemiplegic migraine, hereditary haemorrhagic telangiectasia, vascular Ehlers—Danlos syndrome, Marfan syndrome, psuedoxanthoma elasticum, arterial tortuosity syndrome, Loeys—Dietz syndrome, polycystic kidney disease; neurofibromatosis type 1 von Ricklinghausen disease , Carney syndrome facial lentiginosis and myxoma.
Cortical and subcortical stroke-like lesions, microcystic cavitation, cortical petechial haemorrhages, gliosis, WML. Paraproteinaemia, coagulopathies antiphospholipid antibodies, SLE, nephrotic syndrome, Sneddon syndrome, deficiencies in clotting cascade factors, e. Subarachnoid haemorrhage, migraine-related strokes, paroxysmal hypertension, drug-induced vasoconstriction. Data summarised from several source references [ 28 , 52 , 53 , 88 ]. 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.
VCI came into existence to empower a single label for all conditions in any cognitive domain that has a vascular origin or impaired brain perfusion [ ]. While useful, it is challenging to consistently correlate the degree of pathological changes with the degree of impaired cognition in the continuum of VCI [ 65 , 72 , ]. The description vascular cognitive disorder [ ] also incorporates a continuum comprising cognitive disorders of vascular aetiology with diverse pathologies and clinical manifestations.
Therefore, in the most recent diagnostic and statistical manual of mental disorders DSM or DSM-V criteria and guidelines, the categories of mild and major vascular cognitive disorders were introduced [ 8 ]. Vascular cognitive disorder indicated a global diagnostic category, restricting the term VCI to patients whose cognitive impairment fell short of dementia [ ].
The major neurocognitive disorder classification, meant to describe frank dementia as a substitute for VaD, appears to fit better with patients and more adapted to neurodegenerative cognitive disorders for which memory impairment is not predominant, but comprises substantial frontal lobe pathology [ ]. Cognitive impairment or dementia following stroke is recognised to be relatively common [ , ]. Incident dementia after stroke or post-stroke dementia PSD has become better defined in recent years. PSD may develop within 3 months or after a stabilisation period of a year or longer after stroke injury [ 4 , 16 , ].
However, PSD can have a complex aetiology with varying combinations of large and SVD as well as non-vascular pathology. Atherosclerosis basal, peripheral or meningeal , large infarcts, haemorrhage, herniation, malformations, atrophy. Small vessel disease changes: lipohyalinosis; fibroid necrosis, hyalinisation, collagenosis.
Lacunes and lacunar infarcts: etat lacunaire and etat crible grey and WM. Leukoencephalopathy WMD : anterior vs.
Alzheimer pathology NFT, neuritic plaque staging. The routine includes looking for sites and volumes of haemorrhages, herniation, malformations, swelling or oedema and atrophy. Any extradural, subdural or subarachnoid haemorrhage s that has occurred should be noted. There may be signs of ruptured aneurysms, cortical lacerations, burst intracranial haemorrhage and leakage of intraventricular haemorrhage through the cerebellar foramina.
The basal cerebral arteries and vertebro-basilar arteries and the main branches can be checked for the degrees of atheroma and the presence of thrombosis. Open branch points, for example, at the trifurcation of the internal carotid and middle cerebral artery are common sites for emboli. Vascular abnormalities may include aneurysms, clips and endovascular coils and malformations.
The leptomeninges should be assessed for thickness and translucency, which may be altered much with age. 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. How was the burden of vascular pathology assessed in ageing and dementia studies? Infarct, small vessel disease arteriolosclerosis , CAA, periarteriolar myelin attenuation with gliosis, leukoencephalopathy. Rochester Epidemiology Project [ 95 ]. Large infarcts, lacunes, assessed bilaterally in grey and white matter , leukoencephalopathy.
Geriatric and Psychiatric Hospitals, Geneva [ 63 ]. Lacunes, cortical microinfarcts diffuse, CAA, focal gliosis, periventricular and deep WM demyelination. Rush Memory and Ageing Project [ ]. HAAS [ , ]. Large infarcts, lacunes, microinfarcts, leukoencephalopathy myelin loss with gliosis , haemorrhages. Adult Changes in Thought study [ , ]. Large infarcts, lacunes, microinfarcts, leukoencephalopathy myelin loss , haemorrhages, atherosclerosis CW , arteriolosclerosis, CAA. Large and small infarcts, lacunes, microinfarcts, arteriolosclerosis, CAA, perivascular hemosiderin leakage, perivascular spaces, leukoencephalopathy myelin loss.
In the past, several proposals were made to better define the diagnostic criteria for VaD [ , ]. These have variable specificities and sensitivities and are not interchangeable with substantial misclassification of dementias [ 35 , 62 , ]. The inclusion of deficits in certain cognitive domains such as memory, which is primary to AD, concurs with the relatively low sensitivity 0.
The three cardinal features of VaD that harmonise with NINDS-AIREN criteria for the clinical diagnosis of probable VaD include 1 acute onset of dementia, demonstrated by impairment of memory and two other cognitive domains, such as orientation, praxis, or executive dysfunction, 2 relevant neuroimaging evidence of cerebrovascular lesions and 3 evidence for a temporal relation between stroke and cognitive loss [ ].
However, when they do occur, inaccuracy of clinically diagnosed VaD is often revealed. Invariably, autopsy findings reveal subjects with AD type of pathological changes [ 45 , 80 , 87 ]. All of the patients with signs of CVD were also found to have some concomitant neurodegenerative disease. There are currently no widely validated criteria for either VCI or vascular cognitive disorder [ 63 , 72 , ]. Unbiased criteria encompassing relevant cognitive domains for VCI still need to be widely evaluated [ 39 , 65 , 72 ].
However, as with AD, definitive diagnosis of VaD is made at autopsy, but appropriate sampling and essential neuropathological examination are necessary to rule out significant other pathological changes associated with different causes of cognitive impairment [ 72 ]. Several factors account for the difficulty in deriving an accurate diagnosis of VaD. These include sampling bias, inadequate sample size and absence of pathological verification in many clinical studies; the use of non-standard or difficult-to-compare assessment instruments for clinical, neuropsychological, neuroimaging and neuropathological evaluation [ 72 , ]; and, equally important, disagreement over interpretation of data.
More sensitive neuroimaging modalities have increased antemortem recognition of vascular changes in dementia patients, but these have also become harder to interpret, by revealing similar lesions in non-demented individuals. As discussed above, accurate diagnosis is also not straightforward given the heterogeneity of vascular lesions and the inherent issues with standardisation, especially when assessing mixed pathologies [ 63 ].
Depending on the inclinations of the observer, cases of AD with coexistent vascular lesions such as infarcts may be classified variously as VaD, or AD with coexistent vascular pathology, or mixed dementia [ 55 , ]. To derive more accurate prevalence or incidence estimates and pathological diagnosis, uniformity in protocols and appropriate brain sampling at autopsy across different centres are necessary [ 3 , 39 , 63 , 72 , , ]. Although diagnostic criteria for the neuropathological validation of VaD are lacking, neuroimaging and clinicopathological studies have clearly indicated that the threshold for VaD depends on the extent of cerebral damage.
A combination of factors including origin, volume, location and number of lesions contribute to the development of dementia. It is now clear that widespread small ischaemic lesions or multiple microinfarcts [ , ] distributed throughout the CNS correlate better with dementia and are key predictors of cognitive impairment [ 86 ]. Location of lesions may also be more critical than total volume [ 41 , 46 ].
For example, infarction in the left hemisphere disproportionately increases the risk of dementia [ 41 , 64 , , ]. Bilateral infarcts with greater involvement of the dominant hemisphere also increase the risk of dementia after stroke [ 38 , 45 , ]. Relatively few prospective studies have validated criteria for VaD. These criteria were validated in a prospective series of patients with AD and showed that only 1. The Oxford Project to Investigate Memory and Ageing OPTIMA study has recently developed a simple, novel, image-matching scoring system [ ] to relate the extent of SVD with cognitive function in a study of 70 cases with insufficient pathology to meet the criteria for the diagnosis of AD.
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 quantification of the CVD burden in dementia have been proposed [ 39 ]. 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 the clinicopathological correlations.
Schematic diagram of different cerebrovascular pathologies associated with dementia. The proposed Newcastle categorisation includes six subtypes [ 90 ]. In all the above, the age of the vascular lesion s should correspond with the time when the disease began. The post-stroke survivors are usually included in subtypes I — III. While these may not be different from other published subtypes [ 84 ], they are practical and simple to use. Subtype II usually involves descriptions of arteriosclerosis, lipohyalinosis and hypertensive, arteriosclerotic, amyloid or collagen angiopathy.
Subtypes I , II and V may result from aneurysms, arterial dissections, arteriovenous malformations and various forms of arteritis vasculitis. Assessing the neuropathological substrates of VaD involves systematic assessment of parenchymal lesions, including microinfarcts and haemorrhages and the vascular abnormalities that may have caused them to relate to the progression of impairment [ 39 , 90 , , , ].
In addition, systemic factors e. As discussed above, parenchymal abnormalities of neurodegenerative type may be present that are not obviously associated with either vascular disease or systemic factors, i. Alzheimer type or hippocampal lesions. Confirmation of VaD diagnosis is definitive at autopsy derived from appropriate sampling of both cerebral hemispheres and neuropathological examination [ 72 ] to rule out significant pathological changes associated with other dementias.
However, these values may not reflect the true prevalence and incidence rates of VaD due to inconsistencies in diagnostic criteria, sampling methods and subject or country demographics and variation in morbidity and mortality trends. When a range of clinical criteria was applied to sample sizes of 59—, autopsy studies showed that pathologically diagnosed VaD ranges widely from as low as 0.
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 [ 29 , , , ]. Some form of CVD is common among the assortment of all routine autopsies. Stroke is the most frequent CVD disorder with more than causes.
Recent advances in neuroimaging and systematic neuropathological examination have enabled better definitions of clinically diagnosed CVD, which causes cognitive impairment [ 72 ]. The pathological diagnosis of VaD or VCI, however, requires the systematic evaluation of potentially relevant clinical or phenotypic features with particular attention to the timing of events [ 88 ].
It is difficult to define which neuropathological changes and to what degree these contribute to dementia because of the heterogeneous localisation of lesions and the co-existence of other pathologies including neurodegenerative changes such as those in AD. These include the origin and type of vascular occlusion, presence of haemorrhage, distribution of arterial territories and the size of vessels involved. Thus, many brain regions including the territories of the anterior, posterior and middle cerebral arteries, the angular gyrus, caudate and medial thalamus in the dominant hemisphere, the amygdala and hippocampus, as well as the hippocampus have been implicated in VaD.
Factors that define pathology in subtypes of VaD include multiplicity, size, anatomical location, laterality and age of the lesions besides genetic influences and previous existence of systemic vascular disease. Sampling of postmortem brain tissue for assessing vascular pathology. In Newcastle, large sections are taken as indicated by the pink and green blocks identified by the letters.
What is the best strategy for brain sampling? Block sampling is recommended from the middle frontal gyrus, superior and middle temporal gyri, inferior parietal lobule and occipital cortex; in addition, the medulla, pons including locus coeruleus , cerebellar cortex including dentate nucleus , thalamus and subthalamic nucleus, basal ganglia at the level of the anterior commissure, hippocampus and entorhinal cortex, anterior cingulate gyrus and amygdala [ 81 , ] may also be considered. The BrainNet Europe Consortium has previously recommended a sampling strategy that may be adapted for instances when consent is not available to retain the whole brain for diagnostic evaluation [ 2 ].
The minimal sample set for scoring vascular pathology would include sections of the frontal lobe at the level of the olfactory bulbs, the temporal lobe at the level of the anterior hippocampus and the basal ganglia lenticular nucleus and anterior thalamus at the level of the mamillary body [ 39 ]. The posterior hippocampus is included if available. These regions represent relevant cerebral systems involved in cognition and receive blood from each major cerebral arterial supply [ 39 ]. However, as correctly recommended by the BrainNet Consortium [ 3 ], a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible and, at the same time, comparable results between centres.
Visual grading of degree 0—3 scale of stenosis in basal Circle of Willis arteries. Validated by comparison with detailed cross-sectional measurements in vessel segments.
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Myelin index MI ; ratio of loss against total density. Perivascular cuffing 0—3 scale , perivascular cell density in contact or within 0. Information retrieved from several references as shown. This is not an exhaustive list. Small vessel alternations involve arteriolosclerosis and hyalinosis and 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 dementia [ 39 ]. Other features include border zone watershed infarctions, laminar necrosis and cerebral amyloid angiopathy CAA.
In an attempt to evaluate the natural history and staging of CVD, Deramecourt et al. These were followed by perivascular spacing with lacunar and regional microinfarcts infarcts occurring as consequent, but independent processes. In dementia subjects, VaD had the highest total scores of vascular pathology, whereas AD was the second and dementia with Lewy bodies was the last but greater than in ageing controls [ 39 ]. Pathological outcomes of clinically diagnosed VaD. Mixed type 1 revealed large infracts, whereas mixed type 2 predominantly exhibited SVD with microinfarction.
Other included Lewy body disease, dementia, mild Parkinson disease and depression. Clinicopathological studies also suggest that vascular disease not only influences the burden of the neurodegenerative lesion [ , ]. The density of neocortical plaques was lower in AD cases with coexistent vascular lesions interpreted as contributing to dementia [ ].
In the Religious Order study, elderly nuns who exhibited coexistent AD and brain infarcts at autopsy had poorer cognitive function and a higher prevalence of dementia than those without vascular change [ ]. Compared with pure AD, the lower burden of Alzheimer-type pathology, particularly fewer neurofibrillary tangles, was required to reach the threshold for dementia when there were concomitant lacunar infarcts in subcortical structures including the basal ganglia, thalamus or deep WM.
Similarly, in another religious order study, after accounting for AD lesion burden, the presence of other pathologies or infarcts increased the odds of dementia over fivefold [ ] and caused earlier onset of dementia [ 47 ]. Large infarction or macroinfarction should be visible upon gross examination of the brain at autopsy. Stenosis arising from atherosclerosis within large vessels is considered the main cause of large infarction, which may sometimes extend beyond the arterial territories.
The stages of atherosclerosis may vary from accumulation of foam cells causing fatty streaks to complicated atheromas involving extracellular matrix components and even viral or bacterial infections [ 88 ]. Typical atherosclerosis or microatheromatous disease in the meningeal and smaller vessels, beyond the circle of Willis involving the proximal segments of the middle and anterior cerebral arteries, is generally rare, but may be found in very old subjects [ 91 ].
The presence of dolichoectasia and fusiform aneurysms has also been noted in some cases. In severe cases, medium-sized arteries in the leptomeninges and proximal perforating arteries are involved. The damage could be worse depending on the presence of hypertension. Arterial territorial infarctions involve four principal areas, particularly those supplied by the major arteries: anterior, middle cerebral artery, posterior artery and the territory between the anterior and middle cerebral artery.
The intensity of gliosis, both astrocytic and microgliosis, is an important consideration in judging the degree and age of infarction. However, there is no clear evidence to suggest these are related to cognitive impairment. Degrees of gliosis or glial scars are noted in brains subjected to global ischaemia, i.
Panels show examples of lacunes, small infarcts and microinfarcts. Section from an year-old man with vascular and neurofibrillary pathology. Moderate gliosis in the surrounding region is also evident in the case in c. They represent small foci of ischaemic necrosis resulting from narrowing or occlusion of penetrating arteries branching directly from larger cerebral arteries [ 56 ].
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Lacunar infarcts are frequently multiple and bilateral and often coexist with other vascular lesions e. Whether single or multiple, they may be asymptomatic, depending on their location and the volume of normal brain tissue lost. Lacunes may also represent small haemorrhages or dilated perivascular spaces without infarction or haemorrhage. A few lacunes may represent healed or re-absorbed as 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, recent meta-analyses suggested there were no pathological differences between symptomatic and asymptomatic patients.
Perivascular oedema and thickening, and inflammation and disintegration of the arteriolar wall were common, whereas vessel occlusion was rare [ 9 ], In neuropathological studies of elderly patients with vascular disease but without evidence of AD or other neurodegenerative pathologies, dementia was associated with severe cribriform change and associated subcortical WM damage and microinfarcts [ 48 , ].
Only leukoencephalopathy was associated with dementia, and large infarcts were associated with VaD. VaD without significant AD pathology shows more severe cribriform change and deep white and grey matter lacunar or microinfarcts than stroke subjects with macroscopic infarcts and elderly subjects without dementia [ ]. However, all these findings were also often accompanied by moderate to severe atherosclerosis.
WM lesions visualised by conventional histopathological staining in a year-old man diagnosed with vascular encephalopathy and VaD. The narrowed lumen arrow is seen. Braak staging was graded as IV, but there were no neuritic or cored plaques. The area of hypersignal can be seen in the WM asterisk. A small cortical infarct is also seen arrow. Neuroimaging and pathological studies demonstrate that WM hyperintensisties represent degeneration of the WM mostly explained by SVD [ , , ]. There is some controversy whether deep or periventricular lesions are of more importance, but this depends on the definition of boundaries between the periventricular and deep WM if the coursing of the fibres is used as markers [ 96 ].
Lacunar infarcts are produced 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 frequently spared WM disease may comprise several patterns of alterations including pallor or swelling of myelin, loss of oligodendrocytes, damage to axons, cavitations with or without the presence of macrophages and areas of reactive astrogliosis [ ], where the astrocytic cytoplasm and cell processes may be visible with standard stains.
Oligodendrocytes are particularly vulnerable to hypoxic environment created by low perfusion, which in turn may differentially affect myelin as indicated by the remarkable reduction in the ratio of myelin-associated glycoprotein MAG to proteolipid protein 1 PLP1 not only in the WM, but also the cerebral cortex in VaD [ 12 , ]. Lesions in the WM also include spongiosis, i. The affected regions do not have sharp boundaries, in contrast to the plaques of multiple sclerosis.
These changes may be associated with chronic pro-thrombotic endothelial dysfunction in cerebral SVD [ 77 ] also involving the WM [ 23 ]. There may be a cerebral response to the SVD by increasing endothelial thrombomodulin [ 61 ]. The projected misery perfusion due to capillary loss or abnormalities occurring prior to leukoaraiosis corroborates the finding of a chronic hypoxic state in the deep WM [ 51 ], which also releases several growth promoting factors [ ].
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. Conversely, in AD patients with severe loss of cortical neurons, similar WM lesions are not apparent [ 44 ].
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 increases with age, and perivenous collagenosis is increased further in brains with leukoaraiosis [ 22 ]. The presence of apoptotic cells in WM adjacent to areas of leukoaraiosis suggests that such lesions are dynamic, with progressive cell loss and expansion [ 22 ].
Vascular stenosis caused by collagenosis may induce chronic ischaemia or oedema in the deep WM leading to capillary loss and more widespread effects on the brain [ 23 ]. The accumulation of small, even miniscule ischaemic lesions as an important substrate of VaD has been emphasised in recent years [ 86 ]. Microinfarcts are widely accepted to be small lesions visible only upon microscopy Fig. They are estimated to occur in thousands [ ]. Sometimes these may include regions of incomplete infarction or rarefied subacute change.
Microinfarcts have been described as attenuated lesions of indistinct nature occurring in both cortical and subcortical regions. Microvascular infarcts lacunar infarcts and microinfarcts appear central to the most common cause of VaD Fig. Interestingly, in the autopsied older HAAS, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions [ , ].
Microinfarction in the subcortical structures has been emphasised as a substrate of cognitive impairment [ 6 , 86 ] and correlated with increased Alzheimer type of pathology, but cortical microinfarcts also appear to contribute to the progression of cognitive deficits in brain ageing [ 97 ]. CAA and infarcts in a year-old woman with memory loss, confusional state and disorientation. CT on admission showed infarction in the right posterior parieto-occipital region. Small lacunar infarct in the posterior aspect of the left corona radiata, probable area of cortical infarction in the left occipital lobe.
Inset in c , two strongly stained eosinophilic vessels. There were numerous microinfarcts in the frontal, parietal and occipital cortices. Subject only showed sparse cored and diffuse senile plaques and Braak stage II for neurofibrillary pathology.
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Cerebral microbleeds detected by MRI are small, dot-like hypotense abnormalities, have been associated with extravasated haemosiderin derived from erythrocytes, lipohyalinosis and CAA [ 49 ]. Microbleeds are mainly thought to result from hypertensive vasculopathy, but the frequent co-occurrence of lobar microbleeds suggests that the neurodegenerative pathology or CAA is also of importance [ ]. The relevance of this radiological construct is increasingly recognised due to their relation to clinical outcome and occurrence in anti-amyloid vaccination trials [ 69 ].
However, the presence of multiple microbleeds in the context of VaD is related to worse performance on cognitive tests, mainly in psychomotor speed and executive functioning. Since microbleeds are common in cognitively normal older individuals, attribution of these to VaD should follow a 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 between 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 [ 83 ].
Greater putamen haemosiderin was significantly associated with indices of small vessel ischaemia, including microinfarcts, arteriolosclerosis and perivascular spacing and with lacunes in any brain region but not large vessel disease, or whole brain measures of neurodegenerative pathology.
Higher levels of putamen haemosiderin were correlated with more microbleeds upon MR imaging, but it is possible that brain iron homoeostasis and small vessel ischaemic change are responsible for these rather than only as a marker for minor episodes of cerebrovascular extravasation. Neuroimaging studies have shown that medial temporal lobe and hippocampal atrophy are associated with VaD [ 14 , 54 ] and SVD [ , ], albeit not to the same extent as in AD [ 26 ]. Pathological evidence shows that ischaemic VaD and SVD are also associated with hippocampal changes and atrophy remote to ischaemic injury [ , ].
The focal loss of CA1 neurons in ischemic VaD has been related to lower hippocampal volume and memory score [ ], but the degree of loss appears less in VaD [ 98 ] than in AD. However, selective hippocampal neuronal shrinkage is also an important substrate for VaD.
Alzheimer's Diagnostic Guideline Validation: Exploration of Next Steps: Workshop Summary
This is also evident in delayed dementia after stroke in the absence of any neurodegenerative pathology [ 59 ]. Thus, there is a clear vascular basis for hippocampal neurodegeneration and concurs with the neuroimaging observations of hippocampal atrophy even in population-based incident VaD [ ]. The simplest mechanistic explanation for the atrophy is that the neuronal or dendritic arbour results in subsequent loss in connectivity, which contributes to brain structural and functional changes.
This is consistent with the finding that soluble synaptophysin was decreased in VaD as well as AD. It is characterised by severe cell loss with the CA fields in the presence or absence of microinfarction and gliosis that is not explained by AD. Wizemann , B. Aging 32 suppl. Morris , D. Selkoe , Neurobiol.
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