Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease

Abstract

Vascular dementia (VaD) is recognised as a neurocognitive disorder, which is explained by numerous vascular causes in the general absence of other pathologies. The heterogeneity of cerebrovascular disease makes it challenging to elucidate the neuropathological substrates and mechanisms of VaD as well as vascular cognitive impairment (VCI). Consensus and accurate diagnosis of VaD relies on wide-ranging clinical, neuropsychometric and neuroimaging measures with subsequent pathological confirmation. Pathological diagnosis of suspected clinical VaD requires adequate postmortem brain sampling and rigorous assessment methods to identify important substrates. Factors that define the subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes. Atherosclerotic and cardioembolic diseases appear the most common substrates of vascular brain injury or infarction. Small vessel disease characterised by arteriolosclerosis and lacunar infarcts also causes cortical and subcortical microinfarcts, which appear to be the most robust substrates of cognitive impairment. Diffuse WM changes with loss of myelin and axonal abnormalities are common to almost all subtypes of VaD. Medial temporal lobe and hippocampal atrophy accompanied by variable hippocampal sclerosis are also features of VaD as they are of Alzheimer's disease. Recent observations suggest that there is a vascular basis for neuronal atrophy in both the temporal and frontal lobes in VaD that is entirely independent of any Alzheimer pathology. Further knowledge on specific neuronal and dendro-synaptic changes in key regions resulting in executive dysfunction and other cognitive deficits, which define VCI and VaD, needs to be gathered. Hereditary arteriopathies such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or CADASIL have provided insights into the mechanisms of dementia associated with cerebral small vessel disease. Greater understanding of the neurochemical and molecular investigations is needed to better define microvascular disease and vascular substrates of dementia. The investigation of relevant animal models would be valuable in exploring the pathogenesis as well as prevention of the vascular causes of cognitive impairment.

Keywords: Alzheimer’s disease; Cerebral amyloid angiopathy; Cerebrovascular degeneration; Dementia; Neuropathology; Small vessel disease; Vascular dementia.

Fig. 1

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. Cases with extensive WM disease in the absence of significant other features are included under SVD. *Subtype I may result from large vessel occlusion (atherothromboembolism), artery to artery embolism or cardioembolism. 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). AD Alzheimer’s disease, CH cerebral haemorrhage, CVD cerebrovascular disease, MI myocardial infarction, MID multi-infarct dementia, LVD large vessel disease, SIVD subcortical ischaemic vascular dementia, SVD small vessel disease, VCI vascular cognitive impairment, VaD vascular dementia

Fig. 2

Sampling of postmortem brain tissue for assessing vascular pathology. Coronal blocks from one hemisphere (rostral to caudal) of the cerebrum for an ‘ideal’ sample for neuropathological assessment. In Newcastle, large sections are taken as indicated by the pink and green blocks identified by the letters. A minimum sample constituting four to six large blocks including S, Y/W, F/J, G/H, AB/AD and AL can be reliably used to determine the burden of vascular pathology [39]

Fig. 3

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. AD Alzheimer’s disease

Fig. 4

Pathological features associated with SVD in VaD. Panels show examples of lacunes, small infarcts and microinfarcts. a Typical cavitated lacunar lesions (arrow) in the putamen of a 65-year-old man. b WM attenuation in the medial temporal lobe, but sparing of U fibres. Section from an 80-year-old man with vascular and neurofibrillary pathology. c, d Cerebral microvessels with variable hyalinosis, perivascular rarefaction, microinfarcts and perivascular spaces in two different cases. Moderate gliosis in the surrounding region is also evident in the case in c. d Perivascular dilatation (or spacing) in the WM (arrow). Magnification bar a 1 cm, b 500 μm, c, d 100 μm

Fig. 5

WM lesions visualised by conventional histopathological staining in a 69-year-old man diagnosed with vascular encephalopathy (and VaD). a >75 % stenosis in the internal carotid artery 8 mm above the bifurcation. The narrowed lumen (arrow) is seen. b Severe WM changes in the parietal lobe in this patient. Braak staging was graded as IV, but there were no neuritic or cored plaques. c Postmortem T2W magnetic resonance image of a formalin-fixed block from the parietal lobe. The area of hypersignal can be seen in the WM (asterisk). d H&E stained section from the block in c showing severe deep WM pallor in the area of hypertensity (asterisk). A small cortical infarct is also seen (arrow). Magnification bar a 500 mm, b 400 μm, c 1 cm, d 500 μm

Fig. 6

CAA and infarcts in a 92-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. a Lobar haemorrhage in the frontal lobe. b Macroscopical cortical infarcts in both right and left occipital lobes. c, d Cortical and subarachnoidal arterioles showing thickened homogenous eosinophilic walls. Inset in c, two strongly stained eosinophilic vessels. e Aβ immunohistochemistry shows extensive subarachnoidal and cortical amyloid angiopathy. f A cortical microinfarct with haemosiderin. 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. Magnification bar a, b 1 cm, c–f 100 μm